1Department of Pharmacy, Health and Nutritional Sciences, Section of Preclinical and Translational Pharmacology, UCADH, University of Calabria, 87036 Rende, Cosenza, Italy 2Department of Health Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy 3University Consortium for Adaptive Disorders and Head Pain, UCADH, University of Calabria, 87036 Rende, Cosenza, Italy
Abstract Essential oils are complex mixtures of several components endowed with a wide range of biological activities, including antiseptic, anti-inflammatory, spasmolytic, sedative, analgesic, and anesthetic properties. A growing body of scientific reports has recently focused on the potential of essential oils as anticancer treatment in the attempt to overcome the development of multidrug resistance and important side effects associated with the antitumor drugs currently used. In this review we discuss the literature on the effects of essential oils in in vitro and in vivo models of cancer, focusing on the studies performed with the whole phytocomplex rather than single constituents.
Conclusion .From the available literature essential oils seem to have a great potential as anticancer therapeutic agents; however, information regarding their mechanism of action is still lacking and far from being deciphered. Indeed, their complex chemical composition makes it difficult to envisage a single mechanism underlying the entireness of the biological effect, which is likely the sum and/or synergy of the biological activity of each component. For the same reason, data obtained from single components may not necessarily be, in turn, applied to the whole essential oil. On the other hand, the presence in the phytocomplex of numerous constituents that simultaneously interfere with multiple signaling pathway might be the key for overcoming the current limit of chemotherapeutic agents and in particular the development of multidrug resistance.
Although, from the data reviewed in this paper, the use of essential oils in cancer therapy is very promising, the data obtained from in vitro and in vivo preclinical models have, beside obvious strengths, several limitations and cannot always be fully applicable to humans. Furthermore, administration route, as well as potential toxicity, and side effects are rarely taken into account by the reviewed studies making it difficult to predict the translational potential of those data for the clinical setting.
Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling* Estefanía Moreno 1,2,3,† , Clara Andradas 4,5,† , Mireia Medrano 1,2,3,† , María M. Caffarel 4,6 Eduardo Pérez-Gómez 4,5 , Sandra Blasco-Benito 4,5, María Gómez-Cañas 7,2,8 , M Ruth Pazos 7,2 , Andrew J.Irving 9 , Carme Lluís 1,2,3 , Enric I. Canela 1,2,3 , Javier Fernández-Ruiz 7,2,8 , Manuel Guzmán 2,4,8 , Peter J. McCormick 1,2,3,10* , Cristina Sánchez 4,5*
1 Dept. Biochemistry and Molecular Biology, University of Barcelona, 08028 Barcelona, Spain 2 Centro de Investigación Biomédica en Red de Enfe rmedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain 3 Institute of Biomedicine of the University of Barcelona, 08028 Barcelona, Spain 4 Dept. Biochemistry and Molecular Biology I, School of Biology / Instituto Universitario de Investigación en Neuroquímica, School of Medicine, Complutense University, 28040 Madrid, Spain 5 Instituto de Investigación Hospital 12 de Octubre, 28041 Madrid, Spain 6 Present address: Dept. Pathology, University of Cambridge, CB2 1QP Cambridge, UK 7 Dept. Biochemistry and Molecular Biology III / Instituto Universitario de Investigación en Neuroquímica, School of Medicine, Complutense University, 28040 Madrid, Spain 8 Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) 9 Division of Neuroscience, Ninewells Hospital, University of Dundee, DD1 9SY Dundee, UK 10 School of Pharmacy, University of East Anglia, Norwich Research Park, NR4 7TJ Norwich, UK
Abstract The G protein-coupled receptors CB2(CB2R) and GPR55 are overexpressed in cancer cells and human tumors. As a modulation of GPR55 activity by cannabinoids has been suggested, we analyzed whether this receptor participates in cannabinoid effects on cancer cells. Here, we show that CB2R and GPR55 form heteromers in cancer cells, that these structures possess unique signaling properties, and that modulation of these heteromers can modify the antitumoral activity of cannabinoids in vivo . These findings unveil the existence of previously unknown signaling platforms that help explain the complex behavior of cannabinoids and may constitute new targets for therapeutic intervention in oncology.
Department of Immunology, School of Medicine, Keimyung University, Daegu, Korea
Abstract Epigallocatechin-3-gallate (EGCG) is a type of catechin found in green tea. EGCG exhibits a variety of activities, including anti-inflammatory, antidiabetes, antiobesity, and antitumor. In this review, we focus on the antitumor effects of EGCG. EGCG inhibits carcinogen activity, tumorigenesis, proliferation, and angiogenesis, and induces cell death. These effects are associated with modulation of reactive oxygen species (ROS) production. Although EGCG has a dual function of antioxidant and pro-oxidant potential, EGCG-mediated modulation of ROS production is reported to be responsible for its anticancer effects. The EGCG-mediated inhibition of nuclear factor-κB signaling is also associated with inhibition of migration, angiogenesis, and cell viability. Activation of mitogen-activated protein kinases activity upregulates the anticancer effect of EGCG on migration, invasion, and apoptosis. In addition, EGCG could also induce epigenetic modification by inhibition of DNA methyltransferase activity and regulation of acetylation on histone, leading to an upregulation of apoptosis. Although EGCG promotes strong anticancer effects by multiple mechanisms, further studies are needed to define the use of EGCG in clinical treatment.
Enterohepatic recirculation of bioactive ginger phytochemicals is associated with enhanced tumor growth-inhibitory activity of ginger extract Sushma R.Gundala†, Rao Mukkavilli1,†, Chunhua Yang†,Pooja Yadav2, Vibha Tandon2, Subrahmanyam Vangala1, Satya Prakash3 and Ritu Anej a*Department of Biology, Georgia State University, Atlanta, GA 30303, USA, 1Advinus Therapeutics, Bangalore, Karnataka 560058, India, 2Department of Chemistry, University of Delhi, Delhi 110007, India and 3Department of Biomedical Engineering, McGill University, Montreal, Quebec H3G 1Y6, Canada Abstract
Phytochemical complexity of plant foods confers health-promot-ing benefits including chemopreventive and anticancer effects. Isolating single constituents from complex foods may render them inactive, emphasizing the importance of preserving the natural composition of whole extracts. Recently, we demonstrated in vitrosynergy among the most abundant bioactive constituents of gin-ger extract (GE), viz., 6-gingerol (6G), 8-gingerol (8G), 10-gingerol (10G) and 6-shogaol (6S). However, no study has yet examined the in vivo collaboration among ginger phytochemicals or evaluated the importance, if any, of the natural ‘milieu’ preserved in whole extract. Here, we comparatively evaluated in vivo efficacy of GE with an artificial quasi-mixture (Mix) formulated by combining four most active ginger constituents at concentrations equivalent to those present in whole extract. Orally fed GE showed 2.4-fold higher tumor growth-inhibitory efficacy than Mix in human pros-tate tumor xenografts. Pharmacokinetic evaluations and bioavail-ability measurements addressed the efficacy differences between GE and Mix. Plasma concentration-time profiles revealed multiple peaking phenomenon for ginger constituents when they were fed as GE as opposed to Mix, indicating enterohepatic recirculation. Bioavailability of 6G, 8G, 10G and 6S was 1.6-, 1.1-, 2.5- and 3.4-fold higher, respectively, when dosed with GE compared with Mix. In addition, gingerol glucuronides were detected in feces upon intravenous administration confirming hepatobiliary elimination. These data ascribe the superior in vivo efficacy of GE to higher area under the concentration time curves, greater residence time and enhanced bioavailability, of ginger phytochemicals, when fed as a natural extract compared with artificial Mix, emphasizing the usefulness of consuming whole foods over single agents. ....... In conclusion, our study emphasizes the existence of a complex collaborative interplay among GE phytochemicals to confer maxi-mum therapeutic benefits due to its favorable absorption kinetics and bioavailability. Our observations of possible EHR of gingerols, when delivered in their natural matrix, are compelling and provide impetus to investigate and design futuristic combinations/dietary supplements for prostate cancer management Source : Journal Carcinogenesis Link to Full Article
Epigenetics: A New Link Between Nutrition and Cancer
Emerging studies suggest that dietary components can affect gene expression through epigenetic mechanisms. Epigenetic modifications are heritable and potentially reversible changes in gene expression that do not require changes in the DNA sequence. The main mechanisms of epigenetic control in mammals are DNA methylation, histone modifications, and RNA silencing. The potential reversibility of epigenetic changes suggests that they could be modulated by nutrition and bioactive food compounds. Thus, epigenetic modifications could mediate environmental signals and provide a link between susceptibility genes and environmental factors in the etiology of cancer. Elucidating the impact of nutrition on epigenetic mechanisms may serve as a tool to predict an individuals’ susceptibility to cancer, provide dietary recommendations, or provide therapeutic applications of natural compounds against cancer. The optimal duration and the dose necessary for a chemopreventive effect require further studies. There is limited information about tissue specificity and temporal aspects of dietary treatments. Species differences need to be considered when interpreting results from various models. Importantly, molecular mechanisms of bioactive dietary components should be investigated in greater detail in human intervention studies. Although some of these issues remain controversial, this review mainly focuses on promising data that support the developing field of Nutritional Epigenetics.
Conclusion ....The complex interactions among environmental, genetic, and epigenetic factors during cancer development have not yet been fully identified. Elucidating the epigenetic mechanisms that underlie these modifications may serve as a tool to predict the individuals’ genetic susceptibility to cancer, provide dietary recommendations, or provide therapeutic applications of natural compounds against cancer. Taken together, an increasing number of studies support a role of diet in cancer prevention and treatment....
Orange Juice and Cancer Chemoprevention Silvia Isabel Rech Frankeab, Temenouga Nikolova Guechevab, João Antonio Pêgas Henriquescb & Daniel Práab
Abstract Orange juice (OJ) is among the most consumed fruit juices worldwide, and its chemopreventive action is fairly addressed in the literature. This review critically presents the available evidence linking OJ with cancer chemoprevention and on discussing the putative mechanisms and negative health effects. The chemopreventive action of OJ is related to its effect on metabolic enzymes and its antiinflammatory, cytoprotective/apoptotic, hormonal, cell signaling-modulating, antioxidant, and antigenotoxic effects. Most studies on OJ are in vitro, and few are conducted in vivo. Results from in vitro studies must be interpreted carefully because these findings do not consider in vivo bioavailability. However, such results are useful for studying the impact of different processing and storage methods on OJ's chemopreventive effect. Evidence of OJ's chemoprevention in humans is limited. OJ is antimutagenic in bacteria and antigenotoxic in humans and rodents. Studies using rodent cancer models showed that OJ is cancer chemopreventive, influencing either the induction stage or the promotion stage. The composition and, therefore, the chemopreventive action of OJ might be influenced by different cultivars, climates, extraction methods, packaging, storage temperatures, and shelf lives, among other factors. Epidemiological studies and randomized controlled intervention studies in humans evaluating the chemopreventive effect of OJ, taking into consideration variability in OJ composition, are needed
Anticancer Activity of Scutellaria baicalensis and Its Potential Mechanism FEI YE, Ph.D., LI XUI, B.M., JIZU YI, Ph.D., WANDI ZHANG, B.M., and DAVID Y. ZHANG, M.D., Ph.D.
ABSTRACT Objective:Scutellaria baicalensisis a widely used Chinese herbal medicine that historically isused in anti-inflammatory and anticancer therapy. The aim of the study is to determine its ability to inhibit human cancer cells in vitro and to determine whether its anticancer activity is because of the inhibition of prostaglandin E2(PGE2) production that is derived from arachidonicacid through cyclooxygenase-2 (COX-2) pathway.
Methods:Cell lines from the most common human cancers, including squamous cell carcinoma (SCC-25, KB), breast cancer (MCF-7), hepatocellular carcinoma (HepG2), prostate carcinoma (PC-3 and LNCaP), and colon cancer (KM-12 and HCT-15) were tested. The cells were treated with various concentrations of Scutellaria baicalensis(0.1–100 mg/mL) for 72 hours. Percentage of viable cells after treatment was assessed using a trypan blue dye exclusion assay and the level of PGE2 production was determined by enzyme immunoassay (EIA)
Results:Scutellaria baicalensis demonstrated a strong dose-dependent growth inhibition in al lcell lines. Inhibition concentration at 50% (IC50) for HepG2, MCF-7, PC-3, LNCaP, KM-12, HCT-15, KB and SCC-25 cells was 1.1, 0.9, 0.52, 0.82, 1.1, 1.5, 1.0, and 1.2 mg/mL, respectively. Three cell lines (KB, SCC-25, and HepG2) were assessed for the production of PGE2and a high level of extracellular (KB and SCC-25) and intracellular PGE2(HepG2) was noted. In the presence of Scutellaria baicalensis extract, there was a significant decrease of PGE2 in a dose-dependent fashion.
Conclusions:Scutellaria baicalensis strongly inhibits cell growth in all cancer cell lines tested. However, prostate and breast cancer cells (PC-3, LNCaP, and MCF-7) are slightly more sensitive than other type of cancer cells. It also inhibits PGE2 production, indicating that suppression of tumor cell growth may be due to its ability to inhibit COX-2 activity. This study supports the notion of using Scutellaria baicalensisas a novel anticancer agent to treat various cancer
Anti-angiogenic effect of the total flavonoids in Scutellaria barbata D. Don Zhi-Jun Dai, Wang-Feng Lu, Jie Gao, Hua-Feng Kang, Yu-Guang Ma, Shu-Qun Zhang, Yan Diao, Shuai Lin, Xi-Jing Wang and Wen-Ying Wu
Abstract Background Angiogenesis is closely related to the growth, invasion and metastasis of tumors, also considered as the key target of anticancer therapy. Scutellaria barbata D. Don (S. barbata), a traditional Chinese medicine, is being used to treat various diseases, including cancer. However, the antitumor molecular mechanism of S. barbata was still unclear. This study aimed to investigate the inhibitory effects of the total flavones in S. barbata (TF-SB) on angiogenesis.
Methods Human umbilical vein endothelial cells (HUVECs) were treated with various concentrations of TF-SB. Cell viability was examined using the MTT assay. The scratch assay was used to detect the migration of HUVECs after treatment with TF-SB. The ability of HUVECs to form network structures in vitro was demonstrated using the tube formation assay. The chick embryo chorioallantoic membrane assay was performed to detect the in vivo anti-angiogenic effect. The expression of VEGF was measured by the enzyme-linked immunosorbent.
Results Results showed that TF-SB inhibited the proliferation and migration of HUVECs in a dose- dependent manner. Simultaneously, TF-SB significantly suppressed HUVEC angiogenesis in vitro and in vivo. Furthermore, VEGF was downregulated in both HUVECs and MHCC97-H cells after TF-SB treatment.
Conclusion TF-SB could suppress the process of angiogenesis in vitro and in vivo. TF-SB potentially suppresses angiogenesis in HUVECs by regulating VEGF. These findings suggested that TF-SB may serve as a potent anti-angiogenic agent.
Abstract Extracts of green tea and green tea polyphenols have exhibited inhibitory effects against the formation and development of tumors at different organ sites in animals. These include animal models for skin, lung, oral cavity, esophagus, stomach, intestine, colon, liver, pancreas, bladder, mammary gland, and prostate cancers. In addition to suppressing cell proliferation, promoting apoptosis, and modulating signaling transduction, green tea polyphenols, especially (-)-epigallocatechin-3-gallate, also inhibit cell invasion, angiogenesis, and metastasis. This article reviews data on the cancer preventive activities of green tea polyphenols, possible mechanisms involved, and the relationship between green tea consumption and human cancer risk.
Conclusion The inhibitory activities of tea and tea catechins against carcinogenesis have been demonstrated in different animal models. Studies in cell lines have also showed that tea catechins can affect a variety of signaling and metabolic pathways. These molecular events could result in cancer cell growth inhibition, apoptosis, and inhibition of invasion, angiogenesis, and metastasis. These activities and the prevention of carcinogenesis have been demonstrated in animal model, but the cancer preventive activity of tea has not been consistently observed in human studies. This may be due to the relatively lower levels of tea consumption by some human populations (than animal studies) and the various confounding factors in epidemiological studies in different populations. The low bioavailability of tea polyphenols, such as EGCG, is also an issue. For agents with low systematic bioavailability, their direct contact with the digestive tract could be important for their cancer preventive activity. This point should be applicable to the activities of EGCG and polyphenols in many other foods or beverages. This information, as well as the biological properties and activities of tea polyphenols reviewed here, may be useful in design of prospective studies and in the selection of the agent, dosage, and biomarkers for intervention trials. The results of such well-designed studies will provide more definitive information on the possible use of tea for the reduction of cancer risk in different populations.
Curcumin, the Golden Spice From Indian Saffron, Is a Chemosensitizer and Radiosensitizer for Tumors and Chemoprotector and Radioprotector for Normal Organs Ajay Goela & Bharat B. Aggarwalb
Abstract Curcumin (diferuloylmethane), the yellow pigment in Indian saffron (Curcuma longa; also called turmeric, haldi, or haridara in the East and curry powder in the West), has been consumed by people for centuries as a dietary component and for a variety of proinflammatory ailments. Extensive research within the last decade in cell culture and in rodents has revealed that curcumin can sensitize tumors to different chemotherapeutic agents including doxorubicin, 5-FU, paclitaxel, vincristine, melphalan, butyrate, cisplatin, celecoxib, vinorelbine, gemcitabine, oxaliplatin, etoposide, sulfinosine, thalidomide, and bortezomib. Chemosensitization has been observed in cancers of the breast, colon, pancreas, gastric, liver, blood, lung, prostate, bladder, cervix, ovary, head and neck, and brain and in multiple myeloma, leukemia, and lymphoma. Similar studies have also revealed that this agent can sensitize a variety of tumors to gamma radiation including glioma, neuroblastoma, cervical carcinoma, epidermal carcinoma, prostate cancer, and colon cancer. How curcumin acts as a chemosensitizer and radiosensitizer has also been studied extensively. For example, it downregulates various growth regulatory pathways and specific genetic targets including genes for NF-κB, STAT3, COX2, Akt, antiapoptotic proteins, growth factor receptors, and multidrug-resistance proteins. Although it acts as a chemosensitizer and radiosensitizer for tumors in some cases, curcumin has also been shown to protect normal organs such as liver, kidney, oral mucosa, and heart from chemotherapy and radiotherapy-induced toxicity. The protective effects of curcumin appear to be mediated through its ability to induce the activation of NRF2 and induce the expression of antioxidant enzymes (e.g., hemeoxygenase-1, glutathione peroxidase, modulatory subunit of gamma-glutamyl-cysteine ligase, and NAD(P)H:quinone oxidoreductase 1, increase glutathione (a product of the modulatory subunit of gamma-glutamyl-cysteine ligase), directly quench free radicals, and inhibit p300 HAT activity. These preclinical studies are expected to lead to clinical trials to prove the potential of this age-old golden spice for treating cancer patients.
Conclusion Given the shortcomings of current chemotherapy and radiation treatments for cancer management, it is obvious that such treatments in the future must be combined with more effective and safer drugs/compounds. In this regard, given all the encouraging evidence summarized in the previous sections, curcumin seems to be an ideal, safe, and highly effective compound that can be used as an adjunct in such therapeutic strategies. Use of a curcumin-based, anticancer therapeutic strategy would also allow use of lower doses of chemotherapeutic drugs and radiation but still achieve much higher antitumor efficacy and yet lower toxicity and resistance in the management of variety of human cancers. In this context, it may also be important to gain more meticulous insights into identifying cancer stem cells in various solid organ tumors and determine how these differ from normal stem cells and other neoplastic cells within the same tissue. We believe that given the undisputed and encouraging data for curcumin as a safe and effective cancer preventive and newer data as a potential therapeutic agent, combining curcumin with current chemotherapy and/or radiation may also reduce the need for palliative surgery in some instances, as cancers may be stopped before they become invasive and widely metastatic. These effects combined with its ability to prevent depression, fatigue, neuropathic pain, lack of sleep, and lack of appetite, all symptoms that induced by cancer and cancer treatment, makes curcumin an ideal agent for cancer patients."
Ethanol extract of Gleditsia sinensis thorn suppresses angiogenesis in vitro and in vivo Jin-Mu Yi, Jong-Shik Park, Se-Mi Oh, Jun Lee, Jinhee Kim, Dal-Seok Oh, Ok-Sun Bang and No Soo Kim
Abstract Background Gleditsia sinensis thorns have been widely used in traditional Korean medicine for the treatment of several diseases, including obesity, thrombosis, and tumor-related diseases. The aim of the study is to determine the antiangiogenic effect of Gleditsia sinensis thorns in vitro and in vivo in a bid to evaluate its potential as an anticancer drug.
Methods Ethanol extract of Gleditsia sinensis thorns (EEGS) were prepared and used for in vitro and in vivo assays. In vitro antiangiogenic effect of EEGS was determined in HUVEC primary cells by cell migration and tube formation assays. In vivo antiangiogenic effect of EEGS was determined by measuring vessel formation and vascular endothelial cells migrating into the implanted matrigels in nude mice. The angiogenesis-related proteins of which expression levels were altered by EEGS were identified by proteomic analysis.
Results EEGS exerted a dose-dependent antiproliferative effect on HUVEC cells without significant cytotoxicity. Angiogenic properties, such as cell migration and tube formation, were significantly inhibited by EEGS in a dose-dependent manner. New vessel formation was also suppressed by EEGS, as determined by the directed in vivo angiogenesis assays in nude mice. EEGS reduced the expression of proangiogenic proteins, endothelin 1 and matrix metallopeptidase 2, in HUVEC cells.
Conclusions Our findings suggest that EEGS can inhibit angiogenesis by down-regulating proangiogenic proteins, and therefore it should be considered as a potential anticancer drug targeting tumor-derived angiogenesis.
Cancer-Related Stress and Complementary and Alternative Medicine: A Review Kavita D. Chandwani, Julie L. Ryan, Luke J. Peppone, Michelle M. Janelsins, Lisa K. Sprod, Katie Devine, Lara Trevino, Jennifer Gewandter, Gary R. Morrow, and Karen M. Mustian
James P. Wilmot Cancer Center, Department of Radiation Oncology, School of Medicine and Dentistry, University of Rochester Medical Center, Saunders Research Building, 265 Crittenden Boulevard, Office 2.224, Box CU 420658, Rochester, NY 14642, USA
Abstract A cancer diagnosis elicits strong psychophysiological reactions that characterize stress. Stress is experienced by all patients but is usually not discussed during patient-healthcare professional interaction; thus underdiagnosed, very few are referred to support services. The prevalence of CAM use in patients with history of cancer is growing. The purpose of the paper is to review the aspects of cancer-related stress and interventions of commonly used complementary and alternative techniques/products for amelioration of cancer-related stress. Feasibility of intervention of several CAM techniques and products commonly used by cancer patients and survivors has been established in some cancer populations. Efficacy of some CAM techniques and products in reducing stress has been documented as well as stress-related symptoms in patients with cancer such as mindfulness-based stress reduction, yoga, Tai Chi Chuan, acupuncture, energy-based techniques, and physical activity. Much of the research limitations include small study samples and variety of intervention length and content. Efficacy and safety of many CAM techniques and some herbs and vitamin B and D supplements need to be confirmed in further studies using scientific methodology. Several complementary and alternative medicine therapies could be integrated into standard cancer care to ameliorate cancer-related stress.
Conclusion ....CAM is primarily used by cancer patients to relieve disease- and treatment-related side effects. Although many of the symptoms usually subside after treatment, CAM utilization could help maintain a symptom-free and good quality of life during cancer treatment. The word “stress” cannot be over emphasized when associated with cancer experience. Stress reported by cancer patients could potentially alert healthcare providers about the impending negative outcomes of cancer treatments. Most CAM techniques are relatively inexpensive, simple to administer or practice, and encompass the holistic nature of healing. CAM for stress management could restore a patient’s sense of control, maintain quality of life, reduce risk of cancer recurrence, and minimize physician visits. The first prescription following a cancer-related visit with a healthcare provider may be for stress management technique/product. Further research on CAM and stress can help healthcare professionals as well as patients with their understanding of the significance of safe use of integrative modes of treatment, better compliance with conventional treatment, improve treatment outcomes and survival, and possibly reduce the risk of recurrence of cancer. Thus, CAM for stress management could be a critical component of cancer care.
Source : Evidence-Based Complementary and Alternative Medicine, Volume 2012 (2012), Article ID 979213, 15 pages doi:10.1155/2012/979213 Link to Full Article
Antitumor activity and macrophage nitric oxide producing action of medicinal herb, Crassocephalum crepidioides Koh Tomimori1,2, Shinji Nakama1,3, Ryuichiro Kimura1,4, Kazumi Tamaki1, Chie Ishikawa1,4 and Naoki Mori1*
1 Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan 2 Department of Psychiatry, Naha City Hospital, 2-31-1 Furujima Naha, Okinawa, 902-8511, Japan 3 Musashino Research Institute for Immunity, 790 Nishizatozoe, Gusukube, Miyako Island, Okinawa, 906-0106, Japan 4 Transdisciplinary Research Organization for Subtropics and Island Studies, 1 Senbaru Nishihara, Okinawa, 903-0213, Japan
Background Crassocephalum crepidioides, a plant distributed in Okinawa Islands, is known in folk medicine; however, its anticancer activity has not been investigated. The aim of this study was to determine the in vitro and in vivo antitumor activities of C. crepidioides on murine Sarcoma 180 (S-180) and related molecular mechanisms.
Methods The antitumor effect of C. crepidioides was evaluated in S-180-cell-bearing mice. Cell growth was assessed using a colorimetric assay. Nitrite and nitrate levels were measured by colorimetry. The expression levels of inducible NO synthase (iNOS) in murine RAW264.7 macrophages was assessed by reverse transcriptase-polymerase chain reaction. Activation of iNOS promoter was detected by reporter gene. Activation of nuclear factor-κB (NF-κB) was evaluated by electrophoretic mobility shift assay. The role of NF-κB signaling was analyzed using inhibitors of NF-κB and dominant-negative mutants, and Western blot analysis.
Results C. crepidioides extract delayed tumor growth in S-180-bearing mice. However, it did not inhibit S-180 cell growth in vitro. Supernatant of cultured C. crepidioides-stimulated RAW264.7 macrophages was cytotoxic to S-180 cells. This cytotoxicity was associated with nitric oxide (NO) production. NF-κB signaling pathway was crucial for the transcriptional activation of iNOS gene. Isochlorogenic acid, a component of C. crepidioides, induced NF-κB activation and iNOS expression.
Conclusions The results highlight the oncolytic and immunopotentiation properties of C. crepidioides mediated through NF-κB-induced release of NO from macrophages.
Novel substituted methylenedioxy lignan suppresses proliferation of cancer cells by inhibiting telomerase and activation of c-myc and caspases leading to apoptosis
P Giridharan1, S T Somasundaram1, K Perumal1, R A Vishwakarma2, N P Karthikeyan3, R Velmurugan3 and A Balakrishnan1
1Centre for Biotechnology, Anna University, Chennai 600 025, India
2Bio-organic Chemistry Lab, National Institute of Immunology, New Delhi 110 067, India
3Maruthi Biotech, Chennai 600 034, India
Abstract Conventional solvent fractionation and bioactivity based target assays were used to identify a new anti-cancer molecule from Phyllanthus urinaria, a herbal medicinal plant used in South India. At each step of the purification process the different fractions that were isolated were tested for specific anti-proliferative activity by assays measuring the inhibition of [3H]thymidine incorporation, and trypan blue drug exclusion. The ethyl acetate fraction that contained the bioactivity was further purified and resolved by HPLC on a preparative column. The purity of each of the fractions and their bioactivity were checked. Fraction 3 demonstrated a single spot on TLC and showed maximum anti-proliferative activity. This fraction was further purified and the structure was defined as 7'-hydroxy-3',4',5,9,9'-pentamethoxy-3,4-methylene dioxy lignan using NMR and mass spectrometry analysis. The pure compound and the crude ethyl acetate fraction which showed anti-proliferative activities were examined for ability to target specific markers of apoptosis like bcl2, c-myc and caspases and for effects on telomerase. Four specific cancer cell lines HEp2, EL-1 monocytes, HeLa and MCP7 were used in this study. The results indicate that 7'-hydroxy-3',4',5,9,9'-pentamethoxy-3,4-methylene dioxy lignan was capable of inhibiting telomerase activity and also could inhibit bcl2 and activate caspase 3 and caspase 8 whose significance in the induction of apoptosis is well known. We believe that this compound could serve as a valuable chemotherapeutic drug after further evaluations.
Source : British Journal of Cancer (2002) 87, 98–105. doi:10.1038/sj.bjc.6600422 Link to Full Article
Effect of a Japanese Energy Healing Method Known as Johrei on Viability and Proliferation of Cultured Cancer Cells In Vitro Kazuko Abe, BA,* Rie Ichinomiya, BA,* Tatsue Kanai, BA,* and Kenji Yamamoto, PhD
Abstract Objectives: The objective was to explore the effect of a Japanese energy healing method known as Johrei on the viability and proliferation of cultured human cancer cells in vitro.
Design: A randomly selected 96-well plate or a culture dish of various types of human cancer cell lines in culture were exposed to Johrei treatment. For comparison purpose, an equal number of untreated or volunteer-treated cultures were chosen as the control group. Johrei treatment was repeatedly performed at appropriate time intervals over the course of the experiments. Cell viability was examined by a colorimetric assay with a Cell Counting kit. Morphological changes were analyzed by phase-contrast and time-lapse microscopy. Cell proliferation and early and late stages of cell death were also determined with the use of a bromodeoxyuridine (BrdU) cell proliferation assay kit and an Annexin V-FLUOS Staining kit, respectively.
Outcome measures: Quantitative data were presented as means – standard deviation. The outcome measures were the differences in viable cell numbers that remained under healing practice versus control conditions, and the statistical significance of differences in their mean values was assessed.
Results: The viability loss of cultured human cancer cells in the Johrei group was significantly higher than that of either of the control groups, despite the fact that the responsiveness to Johrei varied with different cancer cell types. The proliferation rate of gastric cancer cells exposed to Johrei treatments for 72 hours was more significantly decreased compared with that of the untreated cells, whereas the extent of dying and/or dead cells in the Johrei group was more profound than that of the untreated cells.
Conclusions: These results provide evidence that Johrei treatment induces the viability loss of various cancer cells in vitro, mainly due to the increased cell death and the decreased proliferation.
Source : THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE Volume 18, Number 3, 2012, pp. 221–228 Link to Full Article
A role for transferrin receptor in triggering apoptosis when targeted with gambogic acid Shailaja Kasibhatla,*† Katayoun A. Jessen,* Sergei Maliartchouk,* Jean Yu Wang,* Nicole M. English,* John Drewe,* Ling Qiu,* Shannon P. Archer,* Anthony E. Ponce,* Nilantha Sirisoma,* Songchun Jiang,* Han-Zhong Zhang,* Kurt R. Gehlsen,* Sui Xiong Cai,* Douglas R. Green,‡ and Ben Tseng*
Note - Gambogic acid is a xanthonoid that is derived from the brownish or orange resin from Garcinia hanburyi
Abstract Transferrin receptor (TfR) has been shown to be significantly overexpressed in different types of cancers. We discovered TfR as a target for gambogic acid (GA), used in traditional Chinese medicine and a previously undiscovered link between TfR and the rapid activation of apoptosis. The binding site of GA on TfR is independent of the transferrin binding site, and it appears that GA potentially inhibits TfR internalization. Down-regulation of TfR by RNA interference decreases sensitivity to GA-induced apoptosis, further supporting TfR as the primary GA receptor. In summary, GA binding to TfR induces a unique signal leading to rapid apoptosis of tumor cells. These results suggest that GA may provide an additional approach for targeting the TfR and its use in cancer therapy.
Discussion ...These results report the identification and characterization of a molecule (GA) that specifically targets TfR engaging a previously unreported mechanism of action to induce apoptosis. It appears from this body of work that GA interferes with TfR internalization leading to the initial, and rapid, signal for apoptosis. We also demonstrate that GA and Tf bind to independent sites on the receptor, and it appears that GA is not competed by Tf. These studies also suggest a requirement of GA for TfR-mediated rapid apoptosis because the mere down-regulation of TfR does not activate this pathway. Whether GA causes additional conformational changes in the receptor, thereby recruiting the death machinery in an unprecedented manner, remains to be uncovered.
With our continuing efforts, we suggest that the GA/TfR discovery may lead to a new generation of anti-cancer drugs and targeting mechanisms that will be synergistic with existing treatments. Identifying roles for other adaptor proteins or signaling molecules in this GA-induced TfR pathway will possibly identify additional therapeutic targets.
Luteolin, a flavonoid with potentials for cancer prevention and therapy Yong Lin,1* Ranxin Shi,2# Xia Wang,1,3 and Han-Ming Shen2
1Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest DR., SE, Albuquerque, NM 87108, USA 2Department of Community, Occupational and Family Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Republic of Singapore 3Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China
Abstract Luteolin, 3′,4′,5,7-tetrahydroxyflavone, is a common flavonoid that exists in many types of plants including fruits, vegetables, and medicinal herbs. Plants rich in luteolin have been used in Chinese traditional medicine for treating various diseases such as hypertension, inflammatory disorders, and cancer. Having multiple biological effects such as anti-inflammation, anti-allergy and anticancer, luteolin functions as either an antioxidant or a pro-oxidant biochemically. The biological effects of luteolin could be functionally related to each other. For instance, the anti-inflammatory activity may be linked to its anticancer property. Luteolin's anticancer property is associated with the induction of apoptosis, and inhibition of cell proliferation, metastasis and angiogenesis. Furthermore, luteolin sensitizes cancer cells to therapeutic-induced cytotoxicity through suppressing cell survival pathways such as phosphatidylinositol 3′-kinase (PI3K)/Akt, nuclear factor kappa B (NF-κB), and X-linked inhibitor of apoptosis protein (XIAP), and stimulating apoptosis pathways including those that induce the tumor suppressor p53. These observations suggest that luteolin could be an anticancer agent for various cancers. Furthermore, recent epidemiological studies have attributed a cancer prevention property to luteolin. In this review, we summarize the progress of recent research on luteolin, with a particular focus on its anticancer role and molecular mechanisms underlying this property of luteolin.
Luteolin sensitizes Fas/FasL–induced apoptosis in HepG2 cells through inhibiting Akt Activation and promoting XIAP Degradation Changyan Lu1, Yinqiang Xin1, Yimiao Xu1, Zhihui Zhao1, Jin Fu1, Ying Diao1, Fei Yin1, Lan Luo2* and Zhimin Yin1*
1Jiangsu Province Key Laboratory for Molecular and Medicine Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, P R China 2State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, P R China
Abstract Fas, an important cell surface protein of the TNF receptor superfamily that induces apoptosis through binding Fas ligand or anti-Fas antibodies. Unfortunately, not all Fas-expressing cells are sensitive to its stimulus. Therefore it is important to study the mechanisms that counteract the FasL-induced apoptotic process which are still poorly understood. Luteolin, an important flavonoid present in a variety of edible plants, exhibits a wide spectrum of pharmacologic properties such as anticancer, antioxidant, and anti-inflammatory. Furthermore, much more attention has been turned to the chemosensitizing effect of luteolin on cancer cells death. In this study, we found that luteolin synergistically caused the FasL-induced apoptosis in HepG2 cells. Such potentiation was achieved through inhibiting Akt activation and promoting proteasomal degradation of X-linked Inhibitor of Apoptosis Protein (XIAP) which mediated the survival signals and allow the cells to escape from apoptosis in various human cancers.
Discussion ....Evidences demonstrated that anti-Fas antibodies, rFasL reduce the growth of transplanted solid tumors in vivo experiments in mice and also cause severe damage to the mouse liver at the same time . Therefore, liver injury induced by this agent determined the limitation of their application. In this study, we found that luteolin enhance FasLinduced apoptosis in HepG2 cells, while the L02 cells can be exemped from the cytoxic effects at a sufficient dose level. (Figure 5C) It may therefore be possible that luteolin could widen the therapeutic window, allowing cancer cells killing while protecting liver cells.
*Luteolin rich foods Parsley, thyme, celery, hot peppers, chamomile tea,
1 State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Av. Padre Toma's Pereira S.J., Taipa, Macao SAR, China 2 Institute of Chinese Medical Sciences, University of Macau, Av. Padre Toma's Pereira S.J., Taipa, Macao SAR, China 3 College of Life Sciences, Zhejiang Chinese Medical University, 548 Binwen Rd., Binjiang Dist., Hangzhou 310053, Zhejiang, China 4 College of Pharmacy, Fujian University of Traditional Chinese Medicine, No.1 Huatuo Rd., Shangjie University Town, Fuzhou 350108, Fujian, China
Abstract In recent years, a number of natural products isolated from Chinese herbs have been found to inhibit proliferation, induce apoptosis, suppress angiogenesis, retard metastasis and enhance chemotherapy, exhibiting anti-cancer potential both in vitro and in vivo. This article summarizes recent advances in in vitro and in vivo research on the anti-cancer effects and related mechanisms of some promising natural products. These natural products are also reviewed for their therapeutic potentials, including flavonoids (gambogic acid, curcumin, wogonin and silibinin), alkaloids (berberine), terpenes (artemisinin, β-elemene, oridonin, triptolide, and ursolic acid), quinones (shikonin and emodin) and saponins (ginsenoside Rg3), which are isolated from Chinese medicinal herbs. In particular, the discovery of the new use of artemisinin derivatives as excellent anti-cancer drugs is also reviewed.
Conclusion Natural products such as GA, curcumin, β-elemene et al. derived from Chinese medicinal herbs are potential candidates for anti-cancer therapeutic drugs.
An evaluation of the anticancer activity in Hopea odorata extracts Norizah, A1*, Zakiah, I2 and Wan, Zurinah WN2
1Herbal Medicine Research Centre, Institute for Medical Research, Jalan Pahang 50588 Kuala Lumpur, Malaysia. 2Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 KL, Malaysia
Abstract Possible anticancer characteristics of Hopea Odorata extracts were investigated by cell proliferation and viability studies of cells in culture. The mechanism of action was studied by determining the rate of apoptosis and expression of protein involved in signal transduction. The result indicated that the butanol extract of H. Odorata had selective inhibition to both Hep G2 and Chang cells with IC50 of 20.14 and 377 μg/ml, respectively. Growth inhibition by the extract showed an increased of apoptosis at concentration of 25 μg/ml. Cell study demonstrated morphologic changes characteristic of apoptosis such as chromatin condensation and fragmentation, as well as formation of apoptotic bodies. However, MAPK kinase signal transduction pathway indicated no difference in ERK1 and ERK2 expression level after exposure at varying time. P53 protein level also showed no changes in expression compared to control. In conclusion, the increase in apoptosis observed was not due to changes in MAPK pathways involving ERK1, ERK 2 and p53 but may involve other pathway, which require further investigation.
Source : Journal of Medicinal Plants Research Vol. 6(8), pp. 1382-1388, 29 February, 2012 Link to Full Article
Quality of Life and Related Dimensions in Cancer Patients Treated with Mistletoe Extract (Iscador): A Meta-Analysis Arndt B¨ussing, Christa Raak, and Thomas Ostermann
Center for IntegrativeMedicine, Faculty of Health, University of Witten/Herdecke, Gerhard-Kienle-Weg 4, 58239 Herdecke, Germany
Abstract The aim of this meta-analysis was to determine the effectiveness of the fermented plant extract Iscador, produced from the white-berry European mistletoe, in the treatment of patients with cancer with respect to quality-of-life- (QoL-) associated measures.
Methods.We searched databases such as PubMed/Medline, Excerpta Medica Database (EMBASE), CAMbase, and other for controlled clinical studies on parameters associated with QoL. Outcome data were extracted and converted into standardized mean differences and their standard errors.
Results. Thirteen prospective and controlled studies which met the inclusion/exclusion criteria reported positive effects in favor of the Iscador application. A random-effect meta-analysis estimated the overall treatment effect at standardized mean difference = 0.56 (CI: 0.41 to 0.71, P < .0001). However, the methodological quality of the studies was poor.
Conclusions. The analyzed studies give some evidence that Iscador treatment might have beneficial short-time effects on QoL-associated dimensions and psychosomatic self-regulation
Source : Evidence-Based Complementary and Alternative Medicine Volume 2012, Article ID 219402 Link to Full Article
.Olive oil intake is inversely related to cancer prevalence: a systematic review and a metaanalysis of 13800 patients and 23340 controls in 19 observational studies Theodora Psaltopoulou1*, Rena I Kosti1, Dimitrios Haidopoulos2, Meletios Dimopoulos3 and Demosthenes B Panagiotakos4
Abstract .Dietary fat, both in terms of quantity and quality, has been implicated to cancer development, either positively or negatively. The aim of this work was to evaluate whether olive oil or monounsaturated fat intake was associated with the development of cancer. A systematic search of relevant studies, published in English, between 1990 and March 1, 2011, was performed through a computer-assisted literature tool (i.e., Pubmed). In total 38 studies were initially allocated; of them 19 case-control studies were finally studied (13800 cancer patients and 23340 controls were included). Random effects meta-analysis was applied in order to evaluate the research hypothesis. It was found that compared with the lowest, the highest category of olive oil consumption was associated with lower odds of having any type of cancer (log odds ratio = -0.41, 95%CI -0.53, -0.29, Cohran’s Q = 47.52, p = 0.0002, I-sq = 62%); the latter was irrespective of the country of origin (Mediterranean or non-Mediterranean). Moreover, olive oil consumption was associated with lower odds of developing breast cancer (logOR = -0,45 95%CI -0.78 to -0.12), and a cancer of the digestive system (logOR = -0,36 95%CI -0.50 to -0.21), compared with the lowest intake. The strength and consistency of the findings states a hypothesis about the protective role of olive oil intake on cancer risk. However, it is still unclear whether olive oil’s monounsaturated fatty acid content or its antioxidant components are responsible for its beneficial effects.
Conclusion Nutritional factors play a major role in cancer initiation and development . The present systematic review and meta-analysis of observational studies revealed that,overall, olive oil consumption was associated with lower odds of cancer development. Most prominent results were observed for breast cancer and cancers of the digestive system, while the aforementioned relationship was similar to studies performed in Mediterranean as well as non-Mediterranean countries. Meta-analyses have several weaknesses, due to inherent biases and differences in study designs (different control for residual confounding, different socio-demographic and other lifestyle characteristics that may alter food habits), publication bias, etc ....
MicroRNA, Nutrition, and Cancer Prevention1 Sharon A. Ross* and Cindy D. Davis
Abstract MicroRNA (miRNA) are small noncoding RNA molecules that are involved in post-transcriptional gene silencing. Alterations in miRNA expression are observed in and may underlie many different human diseases, including cancer. In fact, miRNA have been shown to affect the hallmarks of cancer, including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Genetic and epigenetic alterations may explain aberrant miRNA expression in cancer cells and may also contribute to cancer risk. It is now thought that by circulating through the bloodstream, miRNA can exert their effects at distant sites as well as within the cells of origin. Recent evidence suggests that nutrients and other bioactive food components protect against cancer through modulation of miRNA expression. Moreover, dietary factors have been shown to modify miRNA expression and their mRNA targets in various cancer processes, including apoptosis, cell cycle regulation, differentiation, inflammation, angiogenesis, and metastasis as well as pathways in stress response. Herein, we provide a brief overview of dietary modulation of miRNA expression and its potential role in cancer prevention. Understanding the affect of dietary factors on miRNA expression and function may provide insight on prevention strategies to reduce the burden of cancer.
Vitamin C: A Concentration-Function Approach Yields Pharmacology and Therapeutic Discoveries1,2 Mark Levine,* Sebastian J. Padayatty, and Michael Graham Espey
Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1372
A concentration-function approach to vitamin C (ascorbate) has yielded new physiology and pharmacology discoveries. To determine the range of vitamin C concentrations possible in humans, pharmacokinetics studies were conducted. They showed that when vitamin C is ingested by mouth, plasma and tissue concentrations are tightly controlled by at least 3 mechanisms in healthy humans: absorption, tissue accumulation, and renal reabsorption. A 4th mechanism, rate of utilization, may be important in disease. With ingested amounts found in foods, vitamin C plasma concentrations do not exceed 100 mmol/L. Even with supplementation approaching maximally tolerated doses, ascorbate plasma concentrations are always <250 mmol/L and frequently <150 mmol/L. By contrast, when ascorbate is i.v. injected, tight control is bypassed until excess ascorbate is eliminated by glomerular filtration and renal excretion. With i.v. infusion, pharmacologic ascorbate concentrations of 25–30 mmol/L are safely achieved. Pharmacologic ascorbate can act as a pro-drug for hydrogen peroxide (H2O2) formation, which can lead to extracellular fluid at concentrations as high as 200 mmol/L. Pharmacologic ascorbate can elicit cytotoxicity toward cancer cells and slow the growth of tumors in experimental murine models. The effects of pharmacologic ascorbate should be further studied in diseases, such as cancer and infections, which may respond to generation of reactive oxygen species via H2O2
Survival of cancer patients treated with mistletoe extract (Iscador): a systematic literature review. Ostermann T, Raak C, Büssing A.
Abstract BACKGROUND: In Europe, extracts from Viscum album (VA-E), the European white-berry mistletoe, are widely used to treat patients with cancer.
METHODS: We searched several databases such as Cochrane, EMBASE, NCCAM, NLM, DIMDI, CAMbase, and Medline. Inclusion criteria were controlled clinical studies on parameters associated with survival in cancer patients treated with Iscador. Outcome data were extracted as they were given in the publication, and expressed as hazard ratios (HR), their logarithm, and the respective standard errors using standard formulas.
RESULTS: We found 49 publications on the clinical effects of Iscador usage on survival of cancer patients which met our criteria. Among them, 41 studies and strata provided enough data to extract hazard ratios (HR) and their standard errors (Iscador versus no extra treatment). The majority of studies reported positive effects in favour of the Iscador application. Heterogeneity of study results was moderate (I2 = 38.3%, p < 0.0001). The funnel plots were considerably skewed, indicating a publication bias, a notion which is corroborated by statistical means (AC = -1.3, CI: -1.9 to -0.6, p <= 0.0001). A random effect meta-analysis estimated the overall hazard ratio at HR = 0.59 (CI: 0.53 to 0.66, p < 0.0001). Randomized studies showed less effects than non-randomized studies (ratio of HRs: 1.24, CI: 0.79 to 1.92, p = 0.35), and matched-pair studies gave significantly better results than others (ratio of HRs: 0.33; CI: 0.17 to 0.65, p = 0.0012).
CONCLUSIONS: Pooled analysis of clinical studies suggests that adjuvant treatment of cancer patients with the mistletoe extract Iscador is associated with a better survival. Despite obvious limitations, and strong hints for a publication bias which limits the evidence found in this meta-analysis, one can not ignore the fact that studies with positive effects of VA-E on survival of cancer patients are accumulating. Future studies evaluating the effects of Iscador should focus on a transparent design and description of endpoints in order to provide greater insight into a treatment often being depreciated as ineffective, but highly valued by cancer patients.
Source : Center for Integrative Medicine, Faculty of Medicine, University of Witten/Herdecke, Herdecke, Germany Link to full Article
USE OF ISCADOR, AN EXTRACT OF EUROPEAN MISTLETOE (VISCUM ALBUM), IN CANCER TREATMENT: PROSPECTIVE NONRANDOMIZED AND RANDOMIZED MATCHED-PAIR STUDIES NESTED WITHIN A COHORT STUDY Ronald Grossarth-Maticek, Prof Dr med, Dr phil, Helmut Kiene, Dr med, Stephan M. Baumgartner, Dr sc nat, and Renatus Ziegler, Dr rer nat
Context In anthroposophical medicine, total extracts of Viscum album (mistletoe) have been developed to treat cancer patients. The oldest such product is Iscador. Although Iscador is regarded as a complementary cancer therapy, it is the most commonly used oncological drug in Germany. Objective To determine whether Iscador treatment prolongs survival time of patients with carcinoma of the colon, rectum, or stomach; breast carcinoma with or without axillary or remote metastases; or small cell or nonÐsmall-cell bronchogenic carcinoma; and to explore synergies between Iscador treatment and psychosomatic self-regulation. Design Prospective nonrandomized and randomized matched-pair studies nested within a cohort study. Setting General community in Germany. Participants 10226 cancer patients involved in a prospective longterm epidemiological cohort study, including 1668 patients treated with Iscador and 8475 who had taken neither Iscador nor any other mistletoe product (control patients). Intervention Iscador. Main Outcome Measure Survival time.
Conclusion Mistletoe extracts, which contain a complex of oncologically rellevant active substances and exe rt a variety of anticancer effects, appear to prolong surv i val times in patients with various tumor types. In the studies described here, efficacy was observed in patients with rectum carcinoma, colon carcinoma, stomach carcinoma, breast carcinoma (with or without axillary metastases or remote metastases), and small cell and non-small-cell bronchogenic carcinoma. The study findings support the claim of anthroposophical medicine that mistletoe therapy is generally effective for treating cancer, irrespective of tumor type.2 8 Iscador treatment seems to exert general oncological effects that are not confined to specific tumor cells. An important effect of Iscador, according to our findings, is that it can enhance patients self-regulation.
Positive Changes, Increased Spiritual Importance, and Complementary and Alternative Medicine (CAM) Use Among Cancer Survivors Jun J. Mao, Peter F. Cronholm, Emma Stein, Joseph B. Straton, Steven C. Palmer and Frances K. Barg
Abstract Purpose: Spirituality is an important component of the cancer experience. This study aims to assess characteristics of spiritual health following a cancer diagnosis, and evaluate the relationship between spiritual change and the use of complementary and alternative medicine (CAM) among a population-based cohort of cancer survivors.
Method: A mailed, cross-sectional survey was completed by 614 cancer survivors identified through the Pennsylvania Cancer Registry. All subjects were 3 to 4.5 years postdiagnosis. Relationships between various characteristics of spiritual health and CAM use were examined, along with clinical and sociodemographic factors. Results: Although large proportions of individuals reported that having cancer had positively affected their spiritual well-being (eg, 40.3% experienced highly positive spiritual changes, 68% felt a high sense of purpose, 75.9% reported being very hopeful), some individuals experienced negative spiritual change (36.1%) and continued to experience high levels of uncertainty (27.2%). In multivariate analyses, those survivors who felt spiritual life became more important (adjusted odds ratio [AOR] = 1.92, 95% confidence interval (CI) = 1.21-3.04, P = .006), or experienced positive changes resulting from the cancer experience (AOR = 1.99, 95% CI = 1.26-3.15, P = .003), were more likely to use CAM than those who stated otherwise.
Conclusions: Having cancer affects many different aspects of spiritual well-being, both positively and negatively. Positive changes and increased spiritual importance appear to be associated with the use of CAM. Prospective research is needed to test whether integrating CAM into conventional cancer care systems will facilitate positive, spiritually transformative processes among diverse groups of cancer survivors.
Bojungikki-Tang for Cancer-Related Fatigue: A Pilot Randomized Clinical Trial Jong Soo Jeong, MD (KMD), MS1, Bong Ha Ryu, MD (KMD), PhD1, Jin Sung Kim, MD (KMD), PhD1, Jae Woo Park, MD (KMD), PhD1, Won Cheol Choi, MD (KMD), PhD1, and Seong Woo Yoon, MD (KMD), PhD1
Abstract Background: Bojungikki-tang (Bu-Zhong-Yi-Qi-Tang in Chinese or Hochu-ekki-to in Japanese) is a widely used herbal prescription in traditional medicine in China, Japan, and Korea. The aim of this study was to investigate the effectiveness of Bojungikki-tang for cancer-related fatigue.
Methods: A total of 40 patients with cancer-related fatigue were randomized into an experimental or a waiting list control group. Patients in the experimental group were treated with Bojungikki-tang (TJ-41) and patients in the waiting list group remained without any intervention for 2 weeks.
Results: The experimental group showed statistically significant improvements in fatigue level assessed by the Visual Analogue Scale of Global Fatigue (VAS-F) measuring the severity of fatigue (experimental vs control: -1.1 ± 2.1 vs 0.1 ± 0.9, P < .05) and results of Functional Assessment of Cancer Therapy–General (FACT-G), Functional Assessment of Cancer Therapy–Fatigue (FACT-F), and Trial Outcome Index–Fatigue (TOI-F) also showed significant improvements (FACT-G, 3.7 ± 9.9 vs -2.4 ± 9.5, P < .05; FACT-F,8.0 ± 13.6 vs -2.2 ± 14.1, P < .05; TOI-F, 6.5 ± 9.2 vs -0.5 ± 10.9, P < .05).
Conclusions: The results of this study indicate that Bojungikki-tang may have beneficial effects on cancer-related fatigue and quality of lives in cancer patients. More rigorous trials are needed to confirm the efficacy of Bojungikki-tang.
Calcitriol in cancer treatment: From the lab to the clinic Tomasz M. Beer and Anne Myrthue
Abstract 1,25-Dihydroxyvitamin D (calcitriol), the most active metabolite of vitamin D, has significant antineoplastic activity in preclinical models. Several mechanisms of activity have been proposed. These include inhibition of proliferation associated with cell cycle arrest and, in some models, differentiation, reduction in invasiveness and angiogenesis, and induction of apoptosis. Proposed mechanisms differ between tumor models and experimental conditions, and no unifying hypothesis about the mechanism of antineoplastic activity has emerged. Synergistic and/or additive effects with cytotoxic chemotherapy, radiation, and other cancer drugs have been reported. Significantly supraphysiological concentrations of calcitriol are required for antineoplastic effects. Such concentrations are not achievable in patients when calcitriol is dosed daily due to predictable hypercalcemia and hypercalcuria; however, phase I trials have demonstrated that intermittent dosing allows substantial dose escalation and has produced potentially therapeutic peak calcitriol concentrations. Recently, a phase II study reported encouraging levels of activity for the combination of high-dose calcitriol and docetaxel administered on a weekly schedule in patients with androgen-independent prostate cancer. This regimen is now under study in a placebo-controlled randomized trial in androgen-independent prostate cancer and in phase II studies in several other tumor types. Further work is needed to elucidate the molecular mechanisms of antineoplastic activity and optimal clinical applications of calcitriol in cancer.
Conclusions Calcitriol exerts potent antineoplastic activity in a broad range of tumor models. Several mechanisms of activity have been proposed. Growth inhibition and accumulation in G0-G1, associated with transcriptional activation of CDK inhibitors p27Kip1 and/or p21Waf1 has been the most extensively studied mechanism; however, effects on other mitogenic signals, induction of apoptosis, and inhibition of invasiveness and angiogenesis have also been reported. Additive and/or synergistic activity has been reported with cytotoxic chemotherapy, radiation, and other cancer drugs. At present, no unifying hypothesis for calcitriol's anticancer effects has been formulated. Indeed, it is likely that different mechanisms predominate in different neoplasms. The translation of these preclinical finding into patient care had been hampered by predictable hypercalcemia and hypercalcuria when calcitriol is dosed daily. Calcitriol concentrations that, based on preclinical data, are thought to be necessary for antineoplastic activity, are not achievable with conventional daily dosing. In contrast, intermittent administration of calcitriol has allowed substantial dose escalation. This approach has moved forward in clinical trials. Recently, a phase II study reported encouraging levels of activity for the combination of high-dose calcitriol and docetaxel administered on a weekly schedule in patients with AIPC. This regimen is now under study in a placebo-controlled randomized trial. Further work is needed to fully understand the molecular mechanisms of activity and optimal clinical applications of calcitriol in cancer.
Potential applications of curcumin and its novel synthetic analogs and nanotechnology-based formulations in cancer prevention and therapy Murielle Mimeault and Surinder K Batra
Department of Biochemistry and Molecular Biology, College of Medicine, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
Abstract Curcumin has attracted great attention in the therapeutic arsenal in clinical oncology due to its chemopreventive, antitumoral, radiosensibilizing and chemosensibilizing activities against various types of aggressive and recurrent cancers. These malignancies include leukemias, lymphomas, multiple myeloma, brain cancer, melanoma and skin, lung, prostate, breast, ovarian, liver, gastrointestinal, pancreatic and colorectal epithelial cancers. Curcumin mediates its anti-proliferative, anti-invasive and apoptotic effects on cancer cells, including cancer stem/progenitor cells and their progenies, through multiple molecular mechanisms. The oncogenic pathways inhibited by curcumin encompass the members of epidermal growth factor receptors (EGFR and erbB2), sonic hedgehog (SHH)/GLIs and Wnt/β-catenin and downstream signaling elements such as Akt, nuclear factor-kappa B (NF-κB) and signal transducers and activators of transcription (STATs). In counterbalance, the high metabolic instability and poor systemic bioavailability of curcumin limit its therapeutic efficacy in human. Of great therapeutic interest, the selective delivery of synthetic analogs or nanotechnology-based formulations of curcumin to tumors, alone or in combination with other anticancer drugs, may improve their chemopreventive and chemotherapeutic efficacies against cancer progression and relapse. Novel curcumin formulations may also be used to reverse drug resistance, eradicate the total cancer cell mass and improve the anticarcinogenic efficacy of the current anti-hormonal and chemotherapeutic treatments for patients with various aggressive and lethal cancers.
Immunomodulatory Effect of Rhaphidophora korthalsii on Natural Killer Cell Cytotoxicity Swee Keong Yeap,1 Abdul Rahman Omar,1,2 Abdul Manaf Ali,3 Wan Yong Ho,4 Boon Kee Beh,5 and Noorjahan Banu Alitheen1,4
1Institute of Bioscience, Putra University, Malaysia, Serdang, 43400 Selangor, Malaysia 2Department of Veterinary Pathology and Microbiology, Faculty of Veterinary Medicine, Putra University, Malaysia, Serdang, 43400 Selangor, Malaysia 3Faculty of Agriculture and Biotechnology, Sultan Zainal Abidin University, Malaysia (UniSZA), Kota Campus, Jalan Sultan Mahmud, 20400 Kuala Terengganu, Malaysia 4Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Putra University, Malaysia, Serdang, 43400 Selangor, Malaysia 5Department of Bioprocess Technology, Faculty of Biotechnology and Biomolecular Sciences, Putra University, Malaysia, Serdang, 43400 Selangor, Malaysia
Abstract The in vivo immunomodulatory effect of ethanolic extracts from leaves of Rhaphidophora korthalsii was determined via immune cell proliferation, T/NK cell phenotyping, and splenocyte cytotoxicity of BALB/c mice after 5 consecutive days of i.p. administration at various concentrations. Splenocyte proliferation index, cytotoxicity, peripheral blood T/NK cell population, and plasma cytokine (IL-2 and IFN-𝛾) in mice were assessed on day 5 and day 15. High concentration of extract (350 μg/mice/day for 5 consecutive days) was able to stimulate immune cell proliferation, peripheral blood NK cell population, IL-2, and IFN-𝛾 cytokines, as well as splenocyte cytotoxicity against Yac-1 cell line. Unlike rIL-2 which degraded rapidly, the stimulatory effect from the extract managed to last until day 15. These results suggested the potential of this extract as an alternative immunostimulator, and they encourage further study on guided fractionation and purification to identify the active ingredients that contribute to this in vitro and in vivo immunomodulatory activity.
.....In this study, stimulation of the immune system by R. korthalsii methanol extract had significant effects on proliferation, NK cell population, and cytokine expression in the host, which further enhanced the cytolytic activity of the immune cells. Up till now, 5,6-dihydroxyindole (DHI) is the only compound successfully isolated from R. korthalsii. However, role of DHI on the immunomodulatory effect of R. korthalsii methanol extract and the other potential active secondary metabolites that play an important role in this immunostimulatory effect are still unknown. Thus, future study should focus on isolation and evaluation of active metabolites from the extract that contributes to the immunomodulatory effect against the NK cell.
Source : Evidence-Based Complementary and Alternative Medicine Volume 2012 (2012), Article ID 786487, 7 pages doi:10.1155/2012/786487 Link to Full Article
Lapachol: an overview Hidayat Hussain,*a Karsten Krohn,a Viqar Uddin Ahmad,b Ghulam Abbas Miana,c and Ivan Robert Greend
aDepartment of Chemistry, University of Paderborn, Warburger Straße 100, 33098 Paderborn, Germany bH.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan cRiphah Institute of Pharmaceutical Sciences, Riphah Internation University, Islamabad, Pakistan dDepartment of Chemistry, University of the Western Cape, P/Bag X17, Bellville,7530, South Africa
Abstract Lapachol is a naphthoquinone that was first isolated by E. Paterno from Tabebuia avellanedae (Bignoniaceae) in 1882. A wide spectrum of therapeutic activities have been attributed to lapachol or its derivatives viz., anti-abscess, anti-ulcer, antileishmanial, anticarcinomic, antiedemic, anti-inflammatory, antimalarial, antiseptic, antitumor, antiviral, bactericidal, fungicidal, insectifugal, pesticidal, protisticidal, respiradepressant, schistosomicidal, termiticidal, and viricidal. Originally isolated from species of the Bignoniaceae family, lapachol can also be found in other families such as Verbenaceae, Proteaceae, Leguminosae, Sapotaceae, Scrophulariaceae, and Malvaceae. The interesting and most usefull knowledge on lapachol, which is reviewed in this paper, can be used as a starting point in future research endeavors.
Antitumor activity In a 1968 study, lapachol demonstrated highly significant activity against cancerous tumors in rats.39 Then in 1974, the NCI reported that Phase I clinical trials failed to produce a therapeutic effect with lapachol without side effects and discontinued further cancer research.40 In a small study in 1980 with nine patients with various cancers (liver, kidney, breast, prostate and cervix), pure lapachol demonstrated an ability to shrink tumors and reduce feeling of pain caused by these tumors and achieved complete remissions in three of the patients.41 It is believed that the antitumor activity of lapachol may be due to its interaction with nucleic acids. Additionally it has been proposed that interaction of the naphthoquinone moiety between base pairs of the DNA helix occurs with subsequent inhibition of DNA replication and RNA synthesis.42 Although lapachol has some beneficial effects, it is by no means a perfect anticancer drug. Despite the lack of significant toxicity even in large oral dose levels, sufficiently high blood levels were not attained to show a therapeutic effect.43 This led to the termination of further clinical development of lapachol. Because of its antitumor activity, it is an ideal candidate for systematic modification to develop an understanding of its structure-activity relationships and thus eventually to develop analogs with improved activity. Hartwell and Abbott reported44 that out of 68 synthetic analogs only one, 2-(3,7-dimethyl- 2,6-octadienyl)-3-hydroxy-1,4-naphthoquinone (3) (Figure 4), was active against the Walker 256 tumor cell line. One year later a study of Herman43 indicated a high activity against the Walker 256 tumor cell line for 2-(3’,3’-dibromo-2-propenyl)-3-hydroxy-1,4-naphthoquinone (4). In 1975, Linardi et al.44 developed a lapachol analog, 2-(3’-methyl-2-buteny1)-3-(tetraacetyl-β-Dglucopyranosyloxy)- 1,4-naphthoquinone (5), which was effective in increasing the life span by over 80 % in mice inoculated with leukemic cells. Recently, Vargas et al.45 synthesized two lapachol derivatives 6 and 7 (Figure 5) and these compounds were active against lung, breast, melanoma, ovarian, prostate, and renal cancer.
Metastasis is the major process responsible for the death in cancer patients. Balassiano et al.46 analyzed the effects of lapachol on a human cancer cell line and evaluated the potential of this substance as an anti-metastatic drug using an in vivo assay. The results of this study indicated that lapachol, in the maximal non-toxic concentration for HeLa cells of 400 μg/ml (corresponding to 1012 molecules of the drug/cell), induces alterations in the protein profile and inhibits cellular invasiveness, thus representing an important anti-metastatic activity.
Neovascularization is an essential process in tumor development and thus it is conceivable that anti-angiogenic treatment may block tumor growth.77 In angiogenesis, nitric oxide (NO) is an important factor which mediates vascular endothelial cell growth and migration. β-Lapachone has been demonstrated to possess anti-cancer and anti-viral effects. Whether β-lapachone can induce endothelial cell death or has an anti-angiogenic effect is still uncertain.77 Kung et al.77 recently investigated the in vitro effect of β-lapachone on endothelial cells, including the human vascular endothelial cell line, EAhy926, and human umbilical vascular endothelial cells (HUVEC). Kung et al. demonstrated that NO can attenuate the apoptotic effect of β-lapachone on human endothelial cells and suggest that β-lapachone may thus have potential as an antiangiogenic drug.77
Anti-tumor activity by activation of the Mre11-Tel1p G1/S checkpoint
β-Lapachone is an anticancer agent that selectively induces cell death in several human cancer cell lines.79 However the precise mechanism of β-lapachone cytotoxicity is not yet fully understood. Menacho-Marquez and Mauricio79 reported that β-lapachone treatment delayed cell cycle progression at the G1/S transition, incremented phosphorylation of the Rad53p checkpoint kinase and decreased cell survival in the budding yeast, Saccharomyces cerevisiae.79 Furthermore, β-lapachone induced phosphorylation of histone H2A at serine 129. These checkpoint responses were regulated by Mec1p and Tel1p kinases.79 Mec1p was required for Rad53p/histone H2A phosphorylation and cell survival following β-lapachone treatment in asynchronous cultures, but not for the G1 delay. The major and vital conclusion of all those findings indicated that β-lapachone activates a Mre11p-Tel1p checkpoint pathway in budding yeast. Given the conservative nature of the Mre11p-Tel1p pathway, these results suggest that activation of the Mre11-Tel1p checkpoint could be of significance for β-lapachone anti-tumor activity.
Use of β-lapachone in pancreatic cancers
Erik Bey et al.80 discovered that β-lapachone, currently in phase II clinical trials for use in pancreatic cancers, is also effective against NSCLC (Non-Small Cell Lung Cancer). The authors found that NSCLC cells over express endogenous NAD(P)H:quinone oxidoreductase 1 (NQO1), similar to pancreatic cancers. In NQO1-positive cells, β-lapachone induced PARP-1-mediated cell death.80 Typically, PARP-1 facilitates DNA repair by resealing single strand breaks. When NQO1 is confronted with massive DNA damage, such as after β-lapachone treatment, it triggers μ-calpain cell death mechanisms. β-Lapachone was most effective when delivered in short, 2- to 4-h pulses. Downstream, the chemotherapeutic agent killed NSCLC cells independent of cell cycle or p53 status and in the absence of proapoptotic factors, according to the authors.80 Ough et al.81 also found that cytotoxic in vitro effects of β-lapachone were inhibited with coadministration of dicumarol, a specific inhibitor of NQO1. In pre-established human pancreatic tumor xeno grafts in nude mice, β-lapachone demonstrated greater tumor growth inhibition when given intratumorally compared to when complexed with cyclodextrin to increase its bioavailability.81 In another study on β-lapachone, Park et al.82,83 strongly suggested that NQO1 activity in tumors may be further and selectively elevated using either local radiotherapy or hyperthermia, both established cancer treatment modalities, to improve the cytotoxicity of β-lapachone against human cancer cells.82,83,84 7.2.5 Use of β-lapachone in treatment of neuroendocrine tumors Larsson et al.85 studied in vitro drug sensitivity screening using the fluorometric microculture cytotoxicity assay in one human pancreatic carcinoid and two human bronchial carcinoid cell lines. The aim of this study was to investigate drug sensitivity in neuroendocrine tumor cell lines. In addition, a normal human retinal pigment epithelial cell line was used for comparison. A total of 18 drugs, including β-lapachone, with different mechanisms of action were tested. These studies indicated that some of the tested compounds viz., β-lapachone, could possibly be used in clinical trials and demonstrate a therapeutic effect in patients suffering with neuroendocrine tumors.85
Selective necrotic cell death by DNA damaging activity
Most efforts thus far have been devoted to develop apoptosis inducers for cancer treatment. However, apoptotic pathway deficiencies are a hallmark of cancer cells.86 Sun et al.86 proposed that one way to bypass defective apoptotic pathways in cancer cells is to induce necrotic cell death. They showed that selective induction of necrotic cell death can be achieved by activation of the DNA damage response pathways. While β-lapachone induces apoptosis through E2F1 checkpoint pathways, necrotic cell death can be selectively induced by β-lapachone in a variety of cancer cells. Sun et al.86 also found that β-lapachone, unlike DNA damaging chemotherapeutic agents, transiently activates PARP1, a main regulator of the DNA damage response pathway, both in vitro and in vivo. All these data suggested that selective necrotic cell death can be induced through activation of DNA damage response pathways, supporting the idea of selective necrotic cell death as a therapeutic strategy to eliminate cancer cells.86 7.2.7 Use of β-lapachone in apoptosis induction Woo et al.87 studied the effects of β-lapachone on the growth of the human hepatoma cell line HepG2. The results showed that β-lapachone inhibits the viability of HepG2 by inducing apoptosis, as evidenced by the formation of apoptotic bodies and DNA fragmentation.87 Reverse transcription-polymerase chain reactions and immunoblotting results indicated that treatment of cells with β-lapachone resulted in down-regulation of anti-apoptotic Bcl-2 and Bcl-XL and upregulation of pro-apoptotic Bax expression. However, β-lapachone treatment did not affect the inhibitor of apoptosis proteins family and the Fas/FasL system. Taken together, this study indicated that β-lapachone may have potential as a chemopreventive agent for liver cancer.87 given intratumorally compared to when complexed with cyclodextrin to increase its bioavailability.81 In another study on β-lapachone, Park et al.82,83 strongly suggested that NQO1 activity in tumors may be further and selectively elevated using either local radiotherapy or hyperthermia, both established cancer treatment modalities, to improve the cytotoxicity of β-lapachone against human cancer cells.82,83,84
Use of β-lapachone in treatment of neuroendocrine tumors
Larsson et al.85 studied in vitro drug sensitivity screening using the fluorometric microculture cytotoxicity assay in one human pancreatic carcinoid and two human bronchial carcinoid cell lines. The aim of this study was to investigate drug sensitivity in neuroendocrine tumor cell lines. In addition, a normal human retinal pigment epithelial cell line was used for comparison. A total of 18 drugs, including β-lapachone, with different mechanisms of action were tested. These studies indicated that some of the tested compounds viz., β-lapachone, could possibly be used in clinical trials and demonstrate a therapeutic effect in patients suffering with neuroendocrine tumors.85
Selective necrotic cell death by DNA damaging activity
Most efforts thus far have been devoted to develop apoptosis inducers for cancer treatment. However, apoptotic pathway deficiencies are a hallmark of cancer cells.86 Sun et al.86 proposed that one way to bypass defective apoptotic pathways in cancer cells is to induce necrotic cell death. They showed that selective induction of necrotic cell death can be achieved by activation of the DNA damage response pathways. While β-lapachone induces apoptosis through E2F1 checkpoint pathways, necrotic cell death can be selectively induced by β-lapachone in a variety of cancer cells. Sun et al.86 also found that β-lapachone, unlike DNA damaging chemotherapeutic agents, transiently activates PARP1, a main regulator of the DNA damage response pathway, both in vitro and in vivo. All these data suggested that selective necrotic cell death can be induced through activation of DNA damage response pathways, supporting the idea of selective necrotic cell death as a therapeutic strategy to eliminate cancer cells.86
Use of β-lapachone in apoptosis induction
Woo et al.87 studied the effects of β-lapachone on the growth of the human hepatoma cell line HepG2. The results showed that β-lapachone inhibits the viability of HepG2 by inducing apoptosis, as evidenced by the formation of apoptotic bodies and DNA fragmentation.87 Reverse transcription-polymerase chain reactions and immunoblotting results indicated that treatment of cells with β-lapachone resulted in down-regulation of anti-apoptotic Bcl-2 and Bcl-XL and upregulation of pro-apoptotic Bax expression. However, β-lapachone treatment did not affect the inhibitor of apoptosis proteins family and the Fas/FasL system. Taken together, this study indicated that β-lapachone may have potential as a chemopreventive agent for liver cancer.87
Antiproliferation and cell apoptosis inducing bioactivities of constituents from Dysosma versipellis in PC3 and Bcap-37 cell lines Xiaoqiang Xu,1 Xiuhong Gao,1 Linhong Jin,1 Pinaki S Bhadury,1 Kai Yuan,1 Deyu Hu,1 Baoan Song,1 and Song Yang11
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang 550025, China
BACKGROUND: Recently, interest in phytochemicals from traditional Chinese medicinal herbs with the capability to inhibit cancer cells growth and proliferation has been growing rapidly due to their nontoxic nature. Dysosma versipellis as Bereridaceae plants is an endemic species in China, which has been proved to be an important Chinese herbal medicine because of its biological activity. However, systematic and comprehensive studies on the phytochemicals from Dysosma versipellis and their bioactivity are limited.
RESULTS: Fifteen compounds were isolated and characterized from the roots of Dysosma versipellis, among which six compounds were isolated from this plant for the first time. The inhibitory activities of these compounds were investigated on tumor cells PC3, Bcap-37 and BGC-823 in vitro by MTT method, and the results showed that podophyllotoxone (PTO) and 4'-demethyldeoxypodophyllotoxin (DDPT) had potent inhibitory activities against the growth of human carcinoma cell lines. Subsequent fluorescence staining and flow cytometry analysis indicated that these two compounds could induce apoptosis in PC3 and Bcap-37 cells, and the apoptosis ratios reached the peak (12.0% and 14.1%) after 72 h of treatment at 20 μM, respectively.
CONCLUSIONS: This study suggests that most of the compounds from the roots of D. versipellis could inhibit the growth of human carcinoma cells. In addition, PTO and DDPT could induce apoptosis of tumor cells.
Potential of Spice-Derived Phytochemicals for Cancer Prevention
Bharat B. Aggarwal, Ajaikumar B. Kunnumakkara, Kuzhuvelil B. Harikumar, Sheeja T. Tharakan, Bokyung Sung,Preetha Anand
Affiliation Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA
Abstract Although spices have been used for thousands of years and are known for their flavor, taste and color in the food, they are not usually recognized for their medicinal value. Extensive research within the last two decades from our laboratory and others has indicated that there are phytochemicals present in spices thatmay prevent various chronic illnesses including cancerous, diabetic, cardiovascular, pulmonary, neurological and autoimmune diseases. For instance, the potential of turmeric (curcumin), red chilli (capsaicin), cloves (eugenol), ginger (zerumbone), fennel (anethole), kokum (gambogic acid), fenugreek (diosgenin), and black cumin (thymoquinone) in cancer prevention has been established. Additionally, the mechanism by which these agents mediate anticancer effects is also becoming increasingly evident. The current review describes the active components of some of the major spices, their mechanisms of action and their potential in cancer prevention.
Conclusion From the description provided above it is clear that spice-derived phytochemicals have an enormous potential in the prevention and treatment of cancer. They can induce apoptosis, suppress proliferation of tumor cells, inhibit invasion and angiogenesis, and prevent even bone loss. These phytochemicals mediate their effects through multiple targets and yet pharmacologically they are highly safe. More animal studies and clinical trials are needed to prove the usefulness of these agents. Safety, inexpensive cost, years of intake by humans and their efficacy make them ideal agents. Therefore it is not too surprising to note that Vasco de Gama tried to look for these spices almost five centuries ago.
Anticancer Effects of Taiwanofungus camphoratus Extracts, Isolated Compounds and its Combinational use Ying-Chen Chen, Hsio-O Ho, Chin-Hua Su, Ming-Thau Sheu
Taiwanofungus camphoratus is an indigenous mushroom in Taiwan, which has been used as a traditional medicine to treat many health-related problems. Several biological activities have been reported on T. camphoratus ranging from anti-inflammatory antihypertension to anticancer and so on. Cancer is a major cause of death in Taiwan, and unfortunately, there is no satisfied treatment presently. Thus, a review article about the anticancer effect of T. camphoratus would be a great importance. This article reviews anticancer activities being performed with crude extracts and isolated compounds from T. camphoratus and their synergistic effects. The source of T. camphoratus might be from its fruiting bodies, mycelia, and fermented culture broth and be extracted from water, methanol, ethanol, ethyl acetate, or chloroform, which showed versatile anticancer activities. In addition, various compounds have been further purified from these extracts, such as terpenoids, maleic and succinic acids derivatives, polysaccharides, and other compounds, and they also showed potent cytotoxicity. Besides, T. camphoratus not only has cytotoxic effect but also produces synergistic anticancer effect with trichostatin A, lovastatin, and taxol. It is concluded that T. camphoratus could be considered as a potential anticancer agent to make cancer no longer a frightening nightmare. However, clinical trials of T. camphoratus on human subjects are absent, and the involved mechanism remains unclear. Hence, further investigations would be required.
First isolation and characterization of a novel lectin with potent antitumor activity from a Russula mushroom. Zhang G, Sun J, Wang H, Ng TB.
State Key Laboratory for Agrobiotechnology and Department of Microbiology, China Agricultural University, Beijing 100193, China.
To date only a ribonuclease and a protein with anti-HIV-1 reverse transcriptase activity have been isolated from mushrooms of the genus Russula. In this study a novel lectin, with a molecular weight of 32 kDa, and a unique N-terminal sequence different from other lectins, was isolated from the mushroom Russula lepida. It represents the first lectin isolated from Russula mushrooms. The purification scheme involved [([NH.sub.4]).sub.2][SO.sub.4] precipitation, ion exchange chromatography on diethylaminoethyl DEAE-cellulose and SP-Sepharose, and fast protein liquid chromatography-gel filtration on Superdex 75. The hemagglutinating activity of the lectin (RLL) was inhibited by inulin and O-nitrophenyl-[beta]-D-galacto-pyranoside. The lectin was stable at temperatures up to 70 [degrees]C (half of the activity was preserved at 80 [degrees]C), and in the presence of NaOH or HC1 solutions up to a concentration of 12.5 mM. Its hemagglutinating activity was reduced in the presence of [Mn.sup.2+], [Co.sup.2+], and [Hg.sup.2+] ions, and enhanced by [Cu.sup.2+] ions. It exhibited antiproliferative activity toward hepatoma Hep G2 cells and human breast cancer MCF-7 cells with an [IC.sub.50] of 1.6 [micro]M and 0.9 [micro]M, respectively. Daily intraperitoneal injections of RLL (5.0 mg/kg body weight/day for 20 days) brought about 67.6% reduction in the weight of S-180 tumor. RLL was devoid of antifungal, ribonuclease, and HIV-1 reverse transcriptase inhibitory activities.
,,,,,In summary, a lectin with a distinctive N-terminal sequence, sugar specificity, hemagglutinating activity with relatively high thermostability and [Cu.sup.2+] -induced enhancement, and potent antiproliferative and antitumor activities was isolated from R. lepida fruiting bodies. The potent antitumor activity of RLL is remarkable and hopefully it can be developed into an agent for cancer therapy. This report represents an addition to the existing list of mushroom lectins.
Traditional medicinal plants as anticancer agents from Chhattishgarh, India: An overview Ritesh Jain1*, Sanmati K. Jain1
1 SLT institute of Pharmaceutical Sciences, Guru Ghasidas Viswavidyalaya Bilaspur. Chhattisgarh,
Abstract An attempt has been made to review some medicinal plants used for the prevention and treatment of cancer in Chhattisgarh. Information on the name of plants, family, parts used and method of preparation has been collected from Ethanobotanical literatures. Information collected has revealed 53 plants species that are used for treatment of cancer in Chhattisgarh. All these plants were further reviewed for scientific evidence, 33 plants out of 53 plants were found for possess anticancer, cytotoxic or antioxidant activity in various preclinical or clinical studies
Introduction Over the past decade, herbal medicines have become a topic of global importance, making an impact on both world health and international trade. Medicinal plants continue to play a central role in the healthcare system of large proportions of the world’s population . This is particularly true in developing countries, where herbal medicine has a long and uninterrupted history of use. Recognition and development of the medicinal and economic benefits of these plants are on the increase in both developing and industrialized nations. Continuous usage of herbal medicine by a large proportion of the population in the developing countries is largely due to the high cost of Western pharmaceuticals and healthcare. In addition, herbal medicines are more acceptable in these countries from their cultural and spiritual points of view . Every year, millions of people are diagnosed with cancer, leading to death in a majority of the cases.According to the American Cancer Society deaths arising from cancer constitute 2–3% of the annual deaths recorded worldwide .
Recently, a greater emphasis has been given towards the researches on complementary and alternative medicine that deals with cancer management. Plants have long history of use in the treatment of cancer [5-7]. Several studies have been conducted on herbs under a multitude of ethnobotanical grounds [8-11]. For example, Hartwell has collected data on about 3000 plants, those of which possess anticancer properties and subsequently been used as potent anticancer drugs. Plants derived components have played an important role in the development of several clinically useful anticancer agents. These include vinblastine, vincristine, the camptothecin derivatives, topotecan and irinotecan, etoposide, derived from epipodophyllotoxin and paclitaxel (taxol). Several promising new agents are in clinical development based on selective activity against cancer related molecular targets, including flavopiridol and combretastin A4 phosphate, and some agents which failed in earlier clinical studies are stimulating renewed interest. Sixty percent of currently used anticancer agents are derived in one way oranother from natural sources . Use of plants for medicinal remedies is an integral part of the Indian cultural life, and this is unlikely to change in the years to come. Many traditional healers and herbalists in the Chhattisgarh region of India have been treating cancer patients for many years using variousmedicinal plant species [13, 14]. Despite the long history of cancer treatment using herbal remedies, the knowledge and experience of these herbalists have not been scientificallydocumented. Information on traditional herbal practice in the cancer is passed from one generation to the other through oral tradition. Considering the rapid rate of deforestation and loss of biodiversity, there is a need for accurate scientific documentation of the knowledge and experience of these herbalists. Hence, an attempt has been made to review some medicinal plants used for the prevention and treatment of cancer in Chhattisgarh state, India.
Conclusion Medicinal plants maintain the health and vitality of individuals, and also cure various diseases, including cancer without causing toxicity. Plants derived components have played an important role in the development of several clinically useful anticancer agents. In different region of Chhattisgarh many traditional healers use various medicinal plants for treating of various cancer. This review revealed that many of medicinal plants used by traditional healer are reported to have scientific evidence. There is a need to explore the plants which are not reported scientifically by in-vitro or in-vivo screening methods. These plants can provide potential bioactive compounds for the development of new ‘leads’ to combat cancer diseases
Chemistry and Cancer Preventing Activities of Ginseng Saponins and Some Related Triterpenoid Compounds Shoji Shibata Shibata Laboratory of Natural Medicinal Materials c/o Minophagen Pharmaceutical Co. Ltd., Tokyo, Japan
More than 25 dammarane-type tetracyclic triterpenoid saponins have been isolated from ginseng, the root and rhizome of Panax ginseng C.A. Meyer (Araliaceae). The genuine sapogenins of those saponins, 20(S)-protopanaxa-diol and -triol, were identified as 20(S) 12 -hydroxy-and 20(S) 6 ,12 -dihydroxy-dammarenediol-II, respectively. There are two types of preparations from ginseng: white ginseng prepared by drying after peelling off and red ginseng prepared by steaming and drying. Some partly deglycosylated saponins such as ginsenoside Rh-1, Rh-2, and Rg-3 are obtained from red ginseng as artifacts produced during steaming. Several workers studied the metabolic transformation by human intestinal bacteria after oral administration of ginsenoside Rb-1 and Rb-2 and found that the stepwise deglycosylation yielded compound K and finally 20(S)-protopanaxadiol. Ginsenoside Rg-1was converted into 20(S)-protopanaxatriol via ginsenoside Rh-1. Yun et al. in Korea conducted the epidemiological case-control studies of ginseng and suggested its cancer preventing activities. Kitagawa et al. demonstrated in vitro that ginsenosides,especially 20(R)-ginsenoside Rg-3, specifically inhibited cancer cell invasionand metastasis. Azuma et al. found that ginsenoside Rb-2 inhibited tumor angiogenesis, and Kikuchi et al. reported that ginsenoside Rh-2 inhibited the human ovarian cancer growth in nude mice. Recently, ginsenoside Rg-3 was produced as an anti-angiogenic anti-cancer drug in China. The aforementioned reports suggest that less glycosylated protopanaxadiol derivatives are effective in cancer prevention. Apart from Ginseng tetracyclic triterpenoid saponins, some oleanane-type pentacyclic triterpenoid compounds showed the anti-carcinogenic activity in the two-stage anti-cancer-promotion experiments in vitro and in vivo.
....Anti-tumor activities are the properties characteristic not only to Ginseng saponins but also to other pentacyclic triterpenes.It is noteworthy, however, that ginsenosides, tetracyclic dammarane-type triterpenoid saponins, could be applied safely due to their mostly non-toxic and non-hemolytic characteristics. Ginseng has been employed in Chinese medicine and folklore medicine in the Eastern Asia regions without any noticeable side effects for more than 2000 yr. Apart from triterpenoid saponins in ginseng, acetylenic alcohol obtained from Ginseng, especially panaxytriol, showed anti-cancer activity against melanoma B16 when intramuscularly administered
Moringa oleifera Lam. leaves prevent Cyclophosphamide-induced micronucleus and DNA damage in mice Sathya T.N.1*, Aadarsh P.1, Deepa V.1, Balakrishna Murthy P.1
Abstract Chemoprotective effect of ethanolic extract of Moringa oleifera Lam leaves was evaluated on cyclophosphamide (CP)-induced genotoxicity in the mouse. Animals were pre-treated with the extract for seven consecutive days at doses of 250, 500, 1000 and 2000 mg/kg b.w. Micronucleus in bone marrow and comet (DNA damage) in the liver were performed. Cyclophosphamide was administered intra-peritoneally on day 7 and Mice were sacrificed after 24 hours. In CP treated animals, statistically significant induction of micronuclei in polychromatic erythrocytes (PCE) was recorded. However, in the animals pre-treated with the extract, the percentage of CP-induced MN decreased with increasing concentration of the extract. Results of comet assay showed similar decrease in DNA damage in mice pre-dosed with the extract. These results point out to the presence of chemopreventive phytoconstituents in the crude extract offering protection against CP-induced genotoxicity in the mouse.
Introduction Much focus has been laid on the role of dietary constituents as anti-mutagens and anti-carcinogens since they are non-toxic in nature . Moringa species have long been recognized by folk medicine practitioners as having value in tumor therapy . Moringa oleifera Lam. is the most extensively cultivated species of the Moringaceae family, found in various parts of the world. Many phytochemicals have been isolated from various parts of the plant, viz., phenolic compounds such as quercetin and kaempferol, flavonoids, anthocyanins, carotenoids, vitamins, minerals, amino acids, sterols, glycosides and alkaloids. It contains unique group of compounds called glucosinolates and isothiocyanates [3,4]. Recently isothiocyanates and niacimicin from this plant were shown to be potent inhibitors of cancer [5-7].Niazimicin also inhibited tumor promotion in a mouse two-stage DMBA-TPA tumor model. Seed pod extracts of Moringa have been demonstrated to prevent skin tumors in mice . The leaves are highly nutritious, being a significant source of β-carotene, Vitamin C, protein, iron and potassium and have diverse curative properties [9 -17]. Its leaves are also used as nutritional supplement and growth promoters [18-22]. An immuno enhancing polysaccharide  has been reported from the leaves. Rich source of ascorbic acid and flavonoid pigments such as kaempferol, rhamnetin, isoquercitrin, and kaempferitrin in leaves of M. oleifera are known for their antioxidant properties. [24,25]. Ethanolic extract of leaves of M.oleifera have shown antimicrobial activity [26,27]. Radio protective effect of M.oleifera leaves has been established wherein radiation-induced chromosomal aberrations and micronuclei were suppressed by pre-treatment with methanolic extract . Given its rich nutritional value and abundant therapeutic efficiency, we attempted to study the chemo protective effect of Moringa oleifera leaves on CP-induced DNA damage using micronucleus and comet assays. Ethanol was used for extraction of the phytochemicals since it is a regarded as a powerful solvent capable of isolating majority of the plant constituents.........
Discussion The results of the present study clearly show that ethanolic extract of M.oleifera leaves have a dose-dependent modulatory effect on CP-induced micronuclei. Cyclophosphamide metabolizes into its mutagenic intermediate phosphoramide mustard through enzymatic and nonenzymatic metabolic activation. It is initially acted upon by the mixed function oxygenases to form 4-hydroxy-CP which exists as aldophosphamide. Aldophosphamide further metabolizes to form cytotoxic (acrolein and phosphoramide mustard) and non-cytotoxic (4-ketocyclophosphamide, carboxyphosphamide and aldophosphamide) intermediates. The protective effect may be attributed to the potential involvement of the phytomolecules of the extract to interfere with the enzymes participating in the biotransformation of CP to cytotoxic metabolites. Free radical scavenging represents one of the important strategies in antimutagenesis and anticarcinogenesis. Leaves of M. oleifera contain rich amount of antioxidants [36, 37]. It is reported that M.oleifera has 46 antioxidants and 36 anti-inflammatory compounds naturally occurring in it [38-41]. A possible explanation for the protective effect recorded in the present investigation could be the involvement of its antioxidant and scavenging properties. Antioxidants provide protection by scavenging reactive oxidative species (ROS) that damage DNA and initiate diseases such as cancer. Ethanolic extract of M.olerifera leaves have been reported to contain tannins, saponins, flavonoids, glycosides and terpenoids . Antioxidant vitamins, flavonoids, glucosinolates and organo-sulfur compounds have been proven to have antimutagenic or anticarcinogenic potential [42, 43]
Therefore protection against the clastogenic effects of CP could arise from the scavenging ability of M.oleifera leaves to trap hydroxyl radicals originating from metabolites of CP with an OH functional group. A similar decrease in MnPCEs induced by CP has been described for other antioxidants like stobadine, eugenol which possess the potential to protect DNA from reactive oxygen species and metabolism-dependent mutagens . Aqueous and methanolic extract of M. oleifera leaves have been reported only to limited extent for their antioxidant properties . In that regard, the anti-genotoxic effect delivered by the ethanolic extract of M.oleifera leaves could probably be attributed to the appreciable amount of antioxidant constituents. However, such comparative studies need to be conducted. Our study shows that in the mouse micronucleus test M. oleifera ethanolic extract prevents the genotoxic effects of CP when administered for a period of one week. Furthermore, the extract was non-clastogenic because it did not induce chromosome breakage in the bone marrow cells. Similar results were recorded in the comet assay. It reduces the percentage of DNA damage induced by CP in the liver cells. The results show that the extract has anti-genotoxic effects on CP-induced lesions in mice. The present results eventually lead us to conclude that ethanolic extract of M.oleifera leaves possess anti-genotoxic phytoconstituents.
Hepatoprotective effects of berberine on carbon tetrachloride-induced acute hepatotoxicity in rats Yibin Feng1, Ka-Yu Siu1, Xingshen Ye1, Ning Wang1, Man-Fung Yuen2 , Chung-Hang Leung3, Yao Tong1 and Seiichi Kobayashi4
1 School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong SAR, China 2 Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong SAR, China 3 Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, Faculty of Science, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China 4 Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo, Japan
Background Berberine is an active compound in Coptidis Rhizoma (Huanglian) with multiple pharmacological activities including antimicrobial, antiviral, anti-inflammatory, cholesterol-lowering and anticancer effects. The present study aims to determine the hepatoprotective effects of berberine on serum and tissue superoxide dismutase (SOD) levels, the histology in tetrachloride (CCl4)-induced liver injury.
Methods Sprague-Dawley rats aged seven weeks were injected intraperitoneally with 50% CCl4 in olive oil. Berberine was orally administered before or after CCl4 treatment in various groups. Twenty-four hours after CCl4 injection, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, serum and liver superoxide dismutase (SOD) activities were measured. Histological changes of liver were examined with microscopy.
Results Serum ALT and AST activities significantly decreased in a dose-dependent manner in both pre-treatment and post-treatment groups with berberine. Berberine increased the SOD activity in liver. Histological examination showed lowered liver damage in berberine-treated groups.
Conclusion The present study demonstrates that berberine possesses hepatoprotective effects against CCl4-induced hepatotoxicity and that the effects are both preventive and curative. Berberine should have potential for developing a new drug to treat liver toxicity.
Abstract Laboratory research involving berries is a promising example of food-based cancer prevention. Berries contain many known chemopreventive agents such as anthocyanins and ellagitannins that can be greatly concentrated in freeze-dried berry powders. Based on our program of berry research, this commentary presents the first reported stepwise scheme for the preclinical and clinical development of foodstuffs for cancer prevention. Our preclinical work within this scheme includes promising approaches for assessing the chemopreventive potential of berry powder and berry extracts in preclinical model systems, for determining the mechanisms of action of these agents, and for identifying the active constituents in berries. The commentary also presents preliminary results of clinical trials in the oral cavity, esophagus, and colon using various formulations of freeze-dried berries. The relative merits of berry powders, extracts, or individual constituents (anthocyanins) for cancer prevention are also discussed.
Conclusion A major objective of cancer therapy and prevention investigators is to develop individual therapeutic agents that markedly affect the expression of only one or a very few genes. The objective of this approach is to selectively kill specific types of cancer cells with minimal effects on their normal counterparts. In contrast, berry powders contain a mixture of compounds that seem to affect the expression levels of a wide range of cancer-related genes (to lesser extents than therapeutic agents; ref. 40), thus preventing the conversion of premalignant cells to malignancy at doses that cause minimal or no cytotoxicity. In this regard, berries seem to fulfill the requirement of an “ideal” chemopreventive agent (60). The same is undoubtedly true of many other foodstuffs; for example, a freeze-dried aqueous extract of broccoli sprouts was effective at dietary levels in inhibiting chemically induced bladder cancer with no observable toxicity in rats (61).
From a practical standpoint, we have found that high-risk individuals are usually willing to participate in clinical trials of berry formulations, and compliance in these trials is excellent. Moreover, the general public is intrigued with food-based approaches for the prevention of diseases including cancer. With potentially lower toxicity and costs, effective food-based approaches not only would be attractive for developed countries but would also offer greater portability (versus highly synthesized agents) to underdeveloped countries as well. Therefore, in my opinion, food-based approaches with rational developmental schemes such as the one outlined in this commentary should be an integral part of the overall strategies for the prevention of cancer and other diseases.
The future of food-based chemoprevention will benefit, indeed may rely, on the close collaboration and cooperation of basic scientists, nutritional epidemiologists, and clinical researchers. Mechanistic understandings of foodstuffs can only enhance their prospects for successful interventions in human populations at risk of cancer. Indeed, collaborative research of this nature can even help inform directions for the development of molecular-targeted approaches. As a related example, mechanistic studies indicate that the strong cancer-preventive effects of caloric restriction involve inhibition of the mammalian target of rapamycin (62). This information is potentially valuable to the large enterprise of preclinical and clinical development of mammalian target of rapamycin inhibitors.
Cancer Prevention and Treatment with Resveratrol: From Rodent Studies to Clinical Trials
Resveratrol (3,4′,5-trihydroxy-trans-stilbene) is a dietary polyphenol derived from grapes, berries, peanuts, and other plant sources. During the last decade, resveratrol has been shown to possess a fascinating spectrum of pharmacologic properties. Multiple biochemical and molecular actions seem to contribute to resveratrol effects against precancerous or cancer cells. Resveratrol affects all three discrete stages of carcinogenesis (initiation, promotion, and progression) by modulating signal transduction pathways that control cell division and growth, apoptosis, inflammation, angiogenesis, and metastasis. The anticancer property of resveratrol has been supported by its ability to inhibit proliferation of a wide variety of human tumor cells in vitro. These in vitro data have led to numerous preclinical animal studies to evaluate the potential of this drug for cancer chemoprevention and chemotherapy. This review provides concise, comprehensive data from preclinical in vivo studies in various rodent models of human cancers, highlighting
Perspectives for Cancer Prevention With Natural Compounds A.R.M. Ruhul Amin, Omer Kucuk, Fadlo R. Khuri, and Dong M. Shin
From the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA.Corresponding author: Dong M. Shin, MD, Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322
Abstract Cancer is the second leading cause of death in the United States. Despite the estimated 565,650 deaths in 2008 of Americans as a result of cancer, it is mostly a preventable disease. Simply by modification of diet, maintenance of optimum body weight, and regular physical activity, 30% to 40% of all instances of cancer could be prevented. Modification of diet alone by increasing vegetable and fruit intake could prevent 20% or more of all cases of cancer and may potentially prevent approximately 200,000 cancer-related deaths annually. Because of their safety, low toxicity, antioxidant properties, and general acceptance as dietary supplements, fruits, vegetables, and other dietary elements (phytochemicals and minerals) are being investigated for the prevention of cancer. Extensive research over the past several decades has identified numerous dietary and botanical natural compounds that have chemopreventive potential. In this review, we discuss promising natural chemopreventive compounds, their molecular targets, and their mechanisms, which may help the further design and conduct of preclinical and clinical trials.
Conclusion Chemoprevention research has gained momentum through the US Food and Drug Administration approval of tamoxifen and raloxifene for breast cancer risk reduction. Various epidemiological and preclinical findings and the results of several early clinical studies convincingly argue for a definitive role of selected dietary products in the prevention and treatment of cancers. Many of these agents target multiple signal transduction pathways, which vary widely depending on cancer origin. The key challenge to researchers is how best to use this information for effective cancer prevention in populations with different cancer risks. Moreover, low potency and poor bioavailability of dietary agents pose further challenges to scientists. The introduction of synthetic analogs of natural compounds may be a solution for these potency and bioavailability limitations. For example, the synthetic curcumin analog EF24 exhibited approximately 10-fold greater potency than natural curcumin.154 Some natural compounds have exhibited synergism with established chemopreventive agents or with other natural compounds. Since drug-associated toxicity remains a significant barrier for currently available chemotherapeutic and chemopreventive drugs, using natural compounds (which have better safety profiles) as adjuvant therapy with current chemotherapeutic agents may help to mitigate drug-associated toxicities. For example, genistein was found to sensitize prostate cancer to radiation in animal studies122 and a recent clinical trial suggested that soy isoflavones could prevent radiation-induced bladder and bowel adverse effects and erectile dysfunction.188 Because of the advances in our understanding of multistep and field carcinogenesis, the introduction of new technologies for screening and early detection, and the emergence of promising molecularly targeted agents, prevention and therapy are beginning to converge at the level of early-phase clinical trials.189 The future full convergence of prevention-therapy drug development will open new avenues for natural compounds in reducing the public health impact of major cancers. However, more preclinical studies and clinical trials are certainly needed to validate the usefulness of these agents either alone or in combination with existing therapies.
Anti-cancer and potential chemopreventive actions of ginseng by activating Nrf2 anti-oxidative stress/anti-inflammatory pathways Constance Lay-Lay Saw, Qing Wu and Ah-Ng Tony Kong
Abstract This article review recent basic and clinical studies of ginseng, particularly the anti-cancer effects and the potential chemopreventive actions by activating the transcriptional factor, Nuclear factor (erythroid-derived 2)-like 2 factor 2 (Nrf2) anti-oxidative stress / anti-inflammatory pathways. Nrf2 is a novel target for cancer prevention as it regulates the antioxidant responsive element (ARE), a critical regulatory element in the promoter region of genes encoding cellular phase II detoxifying and anti-oxidative stress enzymes. The studies on the chemopreventive effects of ginseng or its components/products showed that Nrf2 could also be a target for ginseng's actions. A number of papers also demonstrated the anti-inflammatory effects of ginseng which could be related to the Nrf2 signalling pathway. Targeting Nrf2 pathway is a novel approach to the investigation of ginseng's cancer chemopreventive actions, including some oxidative stress / inflammatory conditions responsible for the initiation, promotion and progression of carcinogenesis.
Background Ginseng protects the cardiovascular system, stimulates the central nervous system  and possesses anti-cancer activities [2, 3] inhibiting human gastric adenocarcinoma  and human breast carcinoma . Therefore, ginseng is a potential cancer preventive agent .11
Clinical studies on ginseng as adjuvant therapy for cancer Ginseng possesses preventive and therapeutics effects on cancer . Ginseng is used to treat cancer or to reinforce the effects and/or reduce the side effects of chemotherapy . Ginseng polysaccharides and ginsenosides are the main ingredients contributing to anti-cancer action of ginseng . Ginseng boosts the patient’s immunity, suppresses the proliferation of tumour cells, inhibits the formation of new blood vessels in tumours, induces apoptosis of tumour cells, anti-metastasis of tumour and immunomodulation [3, 6].
Conclusion The anti-cancer and chemopreventive actions of ginseng could be exerted through activating the Nrf2 anti-oxidative and anti-inflammatory pathways. Further studies on the effects of ginseng in Nrf2-mediated induction of phase II/antioxidant enzymes would elucidate the action mechanism of ginseng in cancer chemoprevention
The term “complementary and alternative medicine” (CAM) refers to the broad range of health systems, modalities, and practices that are not part of the conventional and politically dominant health system.1, 2 Functionally defined, CAM refers to those interventions that are neither taught widely in medical schools nor generally available in US hospitals. Several practices that are considered CAM in the United States include complex traditional health systems from other cultures, such as traditional Chinese medicine (TCM), as well as components of these systems that are practiced as distinct entities, such as acupuncture.3 The National Center for Complementary and Alternative Medicine (NCCAM) categorizes CAM into the following domains, entire medical systems, such as homeopathy and ayurveda; mind-body medicine, such as meditation and art therapy; biologically based practices, such as herbal and dietary supplements; manipulative and body-based practices, such as chiropractic and massage; and energy medicine, such as biofield therapies and magnets.4 The use of CAM treatments in the United States is substantial, especially among those with chronic medical problems, including cancer. Eisenberg et al. published the first national survey on the use of CAM in 1993, which revealed that 1 in 3 respondents had used an unconventional or CAM treatment in the previous year.2 Follow-up studies confirmed CAM use rates at least that high,5, 6 and most studies suggested that people use these treatments in addition to conventional medical care. Recent data confirm that CAM use continues to be particularly high among those with chronic diseases, such as cancer.7 Studies have indicated that patients tend not to disclose their use of CAM treatments to their conventional physicians, with many patients reporting that they perceive their physicians as unreceptive to the issue.6 One possible explanation for the patient-physician communication gap on this topic is the limited information most physicians have about CAM, especially given its historical absence as a covered subject in conventional Western medical training. In addition, despite a recent surge of interest in CAM from the medical community, including some form of CAM curriculum at a growing number of medical schools,8 evidence-based information on the topic is currently limited.
The field of cancer survivorship research has been steadily growing along with the number of cancer survivors in the United States. When the National Cancer Act was passed in 1971, there were 3 million cancer survivors. Since that time, the number of cancer survivors has more than tripled, with approximately 10.8 million survivors currently in the United States.
One of the arenas in which there has been substantial interest in the use of CAM modalities is in the field of oncology, both during active treatment and in the post-treatment survivorship phase.10–15 The majority of published studies have either focused on the treatment phase or have included both patients and survivors without making a distinction between these phases.
This article is concerned primarily with CAM and cancer survivorship. The use of CAM interventions is a growing area of interest in cancer survivorship research. CAM can be a challenging issue for oncologists, primary care physicians, and other mainstream medical professionals caring for cancer survivors, especially given that survivors are exposed to reams of information on the Internet and in the media that can cause them to stray into territory that may trigger discomfort and concern from their physicians.
Motivations for CAM use are multidimensional, including a desire to improve quality of life,16 enhance immune function,17 cope with pain,18, 19 and decrease anxiety or other psychological symptoms.15, 20 Although a large number of cancer survivors have high stress levels21 and unmet psychosocial needs,22, 23 uptake of conventional supportive programs often is low.24 For myriad reasons, CAM modalities may be seen as desirable options for some survivor groups to address unmet needs.25 Issues related to CAM use may be particularly relevant to diverse groups with culturally based health beliefs, the underserved, and those who experience health disparities in the mainstream healthcare system.26 As the number of cancer survivors increases, it includes more diverse groups who may be using CAM, making it even more important to understand why particular subgroups of survivors are using CAM, what forms of CAM they are using, and whether this use is being integrated into the rest of their care.27 Although, at this point, there has been little formal assessment of patterns and predictors of CAM use among cancer survivors from diverse ethnic groups, some data suggest that CAM use is overall similarly high across ethnic groups, with subgroup variations in patterns of use.25, 28 For example, although use of mind-body therapies is consistently high on the list of commonly used CAM modalities overall, it is particularly high in some minority subgroups such as African Americans.25
There are potential advantages for practitioners to be able to discuss CAM with their patients and, in some cases, to integrate it with conventional care.26 One way of facilitating meaningful discussion would be for oncologists to have a positive platform from which to establish some “common ground” with the CAM-oriented patient. We posit that particular evidence-based mind-body therapies could provide such a platform and serve as a bridge to connect potentially beneficial supportive interventions to patients, while also opening a general dialogue about CAM and the needs that particular patients may be attempting to address with CAM approaches. The results could be an improved physician-patient relationship and an overall improved patient care.26 Mind-body therapies are a chosen platform because several of these therapies have at least some positive supportive data, and many target stress reduction, which is a tangible endpoint that is associated with improved quality of life and better health outcomes. Moreover, such interventions generally are not practiced as an “alternative” to regular oncological care; hence, they can be integrated into the overall cancer survivorship treatment plan with relatively low risk.29
In this article, we review a few mind-body therapies relevant to cancer survivors and provide a rationale for considering these therapies as possible complementary interventions on the basis of presence of supportive data (albeit inconclusive), an applicable theoretical framework, and relative safety. It is often stated in publications that because CAM modalities lack conclusive evidence, they should not be recommended.30 Despite a lack of absolute certainty about efficacy and mechanism of action, we propose a modified perspective that considers potential benefits of supporting the use of certain mind-body therapies in cancer survivor subgroups,.
Psychosocial Stress and Cancer A recent report of cancer incident rates between 1992 and 2004 showed increases in some cancer types and decreases in others, with an overall slight decline of cancer incidence in both sexes.31 At the same time, mortality rates continued to decline.9, 31 Thus, for increasing numbers of patients, the diagnosis of cancer means coping with a chronic illness that has a variable course for an undetermined amount of time. Given the numerous stressful challenges involved with having a cancer diagnosis,32 it is not surprising that as many as one-third of cancer survivors report high stress levels.33, 34 Stress can manifest in a variety of psychological symptoms, such as anxiety and depression,35–40 intrusive cancer-related thoughts (ie, traumatic stress symptoms),41–44 or physical symptoms, such as fatigue,34, 44 increased pain,45 and impaired sleep.46–48 Amplified stress in cancer patients has been associated with increased morbidity and mortality,29, 49–50 decreased immune function,51–54 increased relapse,53 and decreased health-related quality of life.55, 56 Given the known negative impact of stress on cancer patients, stress has become a priority issue in cancer treatment and research.56, 57 Targeting stress-related variables with psychosocial interventions has been an important emphasis in cancer-care models.58–66
Although the conventional approach to addressing high stress levels in cancer survivors has largely been through supportive group programs, there are significant challenges in recruiting participants to these programs, despite availability, particularly in hard-to-reach populations.24 Hence, high levels of unmet psychosocial needs continue to persist among cancer survivors. It has been well established and recognized that there are widespread health disparities that impact on cancer prevention, treatment, survivorship, and palliative care.67 In the field of cancer survivorship research, an emerging body of literature acknowledges the existence of disparities and supports the development of interventions that are sensitive to social, cultural, and economic differences, particularly as these factors influence quality of life.68–70 Some of the selected findings from this research suggest that the survivorship experience varies by ethnicity, sex, and age.71–73 For example, population studies suggest that the ethnic groups that are low users of conventional supportive group interventions may be relatively high users of CAM.25, 28
As the fields of cancer survivorship and health disparities grow, it will be important to access hard-to-reach and underserved populations. Therefore, we need to continue exploring novel interventions and options for support for the growing and diverse population of cancer survivors. Although evidence for most CAM treatments is not clearly established, many of the mind-body therapies that have been used to support cancer patients are generally regarded as safe. We focus our discussion on a few modalities that have a promising basis in evidence to serve as adjunctive interventions for supporting the psychosocial needs of cancer survivors.
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