Decreased Plasma Ascorbate Levels in Stage IV Melanoma Patients T. Schleich1, S. Rodemeister1, S. Venturelli2, T. Sinnberg3, C. Garbe3, C. Busch3
1Department of Pediatrics, University of Tuebingen, Germany
2Institute of Biological Chemistry and Nutrition, University of Hohenheim, Germany
3Department of Internal Medicine I, University of Tuebingen, Germany
4Department of Dermatology, Section of Dermato-Oncology, University of Tuebingen, Germany
Abstract It has been reported that cancer patients frequently express low ascorbate (ascorbic acid, vitamin C) blood levels. However, so far this was not shown for melanoma patients.
Total ascorbate (TAA) levels were determined in plasma of healthy control individuals (n=31, mean age: 47.3 years, TAA: 64.86 µM) and in 126 melanoma patients (stage I: n=30, mean age: 51 years, TAA: 59.95 µM; stage II: n=30, mean age: 46.8 years, TAA: 58.85 µM; stage III: n=32, mean age: 48.6 years, TAA: 57.27 µM; stage IV: n=34, mean age: 51.1 years, TAA: 47.16 µM). Plasma TAA levels in stage IV patients were significantly reduced by 27.3% when compared to healthy individuals (p=0.0001, t-test). The reduced plasma TAA levels in stage IV patients negatively correlated with increased S100 and lactate dehydrogenase (LDH) levels. Further, plasma TAA levels were determined in additional 9 stage IV patients directly before and 24 h after intravenous polychemotherapy (carboplatin+paclitaxel, n=5) or immunotherapy (ipilimumab, n=4). TAA levels significantly decreased 24 h after therapy (mean TAA before therapy: 48.7 µM; mean TAA after therapy: 43.0 µM; 11.4% reduction, p<0.05, t-test).
Ascorbate levels in the plasma of 126 melanoma patients were significantly decreased in the cohort of stage IV patients and were further decreased by polychemo- or immunotherapy in stage IV patients. Considering the importance of adequate ascorbate supply, ascorbate substitution in physiological doses could be considered for late-stage melanoma patients.
Enhancement of the Response of B16F1 Melanoma to Fractionated Radiotherapy and Prolongation of Survival by Withaferin A and/or Hyperthermia Guruprasad Kalthur, PhD1, and Uma Devi Pathirissery, PhD2
Abstract Withaferin A (WA), isolated from Indian medicinal plant Withania somnifera has weak antitumor and radiosensitizing property. The present investigation was planned to evaluate the tumor sensitizing effect of WA with or without local hyperthermia on the response of B16F1 melanoma to fractionated and acute radiotherapy. C57BL mice bearing tumors of 100 ± 10mm3 were treated with fractionated radiotherapy (RT, 2Gy x 5 days/week, 4 weeks), withaferin A (15mg/kg, i.p., 5 days/week, 3 weeks), local hyperthermia (HT, 43°C once a week, 3 weeks) and their combinations, or acute RT (40Gy), WA (40mg/kg), HT (43°C, 30min) and their combinations. Treatment response was studied by tumor regression, growth delay and animal survival. Acute RT+HT produced 50% partial response which increased to 62.5% with combination of WA. In fractionated regimen, trimodality combination resulted in 100% PR. Acute RT+HT and WA+RT produced similar increase in growth delay (GD) compared to RT alone which further increased in trimodality treatment. Fractionated WA+RT+HT for 3 weeks produced a higher GD and survival than all other treatments. In conclusion, WA is a better radiosensitizer than HT in fractionated regimen and the response of radioresistant tumors like melanoma can be significantly enhanced by combining nontoxic doses of WA with fractionated RT, with or without HT, allowing decrease in radiation dose.
Synergistic Effects of Combined Phytochemicals and Skin Cancer Prevention in SENCAR Mice Magdalena C. Kowalczyk, Piotr Kowalczyk, Olga Tolstykh, et al.
Abstract The purpose of our study was to determine the inhibitory effect of combined phytochemicals on chemically induced murine skin tumorigenesis. Our hypothesis was that concurrent topical and dietary treatment with selected compounds would lead to more efficient prevention of skin cancer. We tested ellagic acid and calcium D-glucarate as components of diets, while resveratrol was applied topically; grape seed extract was applied topically or in the diet. The 4-week inflammatory-hyperplasia assay based on the 7,12-dimethylbenz[a]anthracene (DMBA)–induced skin carcinogenesis model in SENCAR mice was used. We have found that all the selected combinations caused a marked decrease of epidermal thickness compared with the DMBA-treated group and also with groups treated with a single compound and DMBA. All combinations of resveratrol with other compounds showed a synergistic effect on hyperplasia and Ha-ras mutations. Skin tissue of mice receiving the combinations showed decreased cell proliferation and Bcl2 expression; decreased p21, a regulator of cell cycle; and decreased marker of inflammation cyclooxygenase-2. All the selected combinations diminished the DMBA-induced mRNA expression of the CYP1B1 level, and also caused a marked decrease of proto-oncogenes c-jun and c-fos, components of transcription factor activator protein. In conclusion, all combinations showed either additive or synergistic effects and their joint actions allowed for decreasing the doses of the compounds. Especially, resveratrol combinations with ellagic acid, grape seed extract, and other phytochemicals are very potent inhibitors of skin tumorgenesis, based on the suppression of epidermal hyperplasia as well as on the modulation of intermediate biomarkers of cell proliferation, cell survival, inflammation, oncogene mutation, and apoptosis.
Phytochemicals as Protectors Against Ultraviolet Radiation: Versatility of Effects and Mechanisms Albena T. Dinkova-Kostova1
1Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Scotland, UK and Department of Pharmacology and Molecular Sciences and Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
Abstract Ultraviolet (UV) radiation is one of the most abundant carcinogens in our environment, and the development of non-melanoma skin cancers, the most common type of human malignancy worldwide, represents one of the major consequences of excessive exposure. Because of growing concerns that the level of UV radiation is increasing as a result of depletion of the stratospheric ozone and climate change, the development of strategies for protection of the skin is an urgent need. Many phytochemicals that belong to various families of secondary metabolites, such as alkaloids (caffeine, sanguinarine), flavonoids [(−)-epigallocatechin 3-gallate, genistein, silibinin], carotenoids (β-carotene, lycopene), and isothiocyanates (sulforaphane), offer exciting platforms for the development of such protective strategies. These phytochemicals have been consumed by humans for many centuries as part of plant-rich diets and are presumed to be of low toxicity, an essential requirement for a chemoprotective agent. Mechanistically, they affect multiple signalling pathways and protect against UV radiation-inflicted damage by their ability to act as direct and indirect antioxidants, as well as anti-inflammatory and immunomodulatory agents. Such ”pluripotent character” is a critical prerequisite for an agent that is designed to counteract the multiple damaging effects of UV radiation. Especially attractive are inducers of the Keap1/Nrf2/ARE pathway, which controls the gene expression of proteins whose activation leads to enhanced protection against oxidants and electrophiles. Such protection is comprehensive, long-lasting, and unlikely to cause pro-oxidant effects or interfere with the synthesis of vitamin D.
Source : Planta Med 2008; 74(13): 1548-1559 DOI: 10.1055/s-2008-1081296 Link to Full Article
Harmine activates intrinsic and extrinsic pathways of apoptosis in B16F-10 melanoma Thayele P Hamsa and Girija Kuttan* Amala Cancer Research Centre, Amala Nagar, Thrissur, Kerala, India, 680555
Abstract Background Harmine is a beta-carboline alkaloid from the plant Peganum harmala. Previous studies found that harmine inhibited metastasis of B16F-10 melanoma cells. This study aims to elucidate the role of harmine in apoptosis of B16F-10 cells.
Methods B16F-10 melanoma cells were treated in the presence and absence of harmine in vitro. Morphological changes, cell cycle and expression of various pro and anti- apoptotic genes were analyzed for the study of apoptosis.
Results Morphological observation and DNA laddering assay showed that harmine treated cells displayed marked apoptotic characteristics, such as nuclear fragmentation, appearance of apoptotic bodies and DNA laddering fragment. TUNEL assay and flow cytometric analysis also confirmed apoptosis. Furthermore, RT-PCR analysis showed that harmine induced apoptosis in B16F-10 melanoma cells by up-regulating Bax and activating Caspase-3, 9 and p53 and down-regulating Bcl-2. Harmine also up-regulated Caspase-8 and Bid, indicating that harmine affected both extrinsic and intrinsic pathways of apoptosis. This study also showed inhibitory effects of harmine on some transcription factors and pro- inflammatory cytokines that protect cell from apoptosis.
Conclusion Harmine activates both intrinsic and extrinsic pathways of apoptosis and regulates some transcription factors and pro-inflammatory cytokines.
In vitro and in vivo anticancer properties of a Calcarea carbonica derivative complex (M8) treatment in a murine melanoma model Fernando SF Guimarães1, Lucas F Andrade1, Sharon T Martins1, Ana PR Abud1, Reginaldo V Sene1, Carla Wanderer1, Inés Tiscornia2, Mariela Bollati-Fogolín2, Dorly F Buchi1, Edvaldo S Trindade1*
Abstract Background: Melanoma
is the most aggressive form of skin cancer and the most rapidly
expanding cancer in terms of worldwide incidence. Chemotherapeutic
approaches to treat melanoma have had only marginal success. Previous
studies in mice demonstrated that a high diluted complex derived from
Calcarea carbonica (M8) stimulated the tumoricidal response of activated
lymphocytes against B16F10 melanoma cells in vitro.
Methods: Here
we describe the in vitro inhibition of invasion and the in vivo
anti-metastatic potential after M8 treatment by inhalation in the B16F10
lung metastasis model.
Results: We
found that M8 has at least two functions, acting as both an inhibitor
of cancer cell adhesion and invasion and as a perlecan expression
antagonist, which are strongly correlated with several metastatic,
angiogenic and invasive factors in melanoma tumors.
Conclusion: The
findings suggest that this medication is a promising non-toxic therapy
candidate by improving the immune response against tumor cells or even
induce direct dormancy in malignancies.
Stimulation of lymphocyte anti-melanoma activity by co-cultured macrophages activated by complex homeopathic medication
Fernando
SF Guimarães, Ana PR Abud, Simone M Oliveira, Carolina C Oliveira,
Beatriz César, Lucas F Andrade, Lucélia Donatti, Juarez Gabardo, Edvaldo
S Trindade, and Dorly F Buchi
Departamento
de Biologia Celular, Laboratório de Pesquisa em Células Inflamatórias e
Neoplásicas, Universidade Federal do Paraná (UFPR), Curitiba – PR,
Brazil Abstract
Background Melanoma
is the most aggressive form of skin cancer, and the most rapidly
expanding cancer in terms of worldwide incidence. Chemotherapeutic
approaches to treat melanoma have been uniformly disappointing. A
Brazilian complex homeopathic medication (CHM), used as an immune
modulator, has been recommended for patients with depressed immune
systems. Previous studies in mice have demonstrated that the CHM
activates macrophages, induces an increase in the number of leukocytes
and improves the murine response against Sarcoma-180
Conclusion Co-culture
of macrophages with lymphocytes in the presence of the CHM enhanced
the anti-cancer performance of lymphocytes against a very aggressive
lineage of melanoma cells. These results suggest that non-toxic
therapies using CHMs are a promising alternative approach to the
treatment of melanomas. In addition, they are attractive
combination-therapy candidates, which may enhance the efficacy of
conventional medicines by improving the immune response against tumor
cells.
Tea Intake and Squamous Cell Carcinoma of the Skin: Influence of Type of Tea Beverages
Iman A. Hakim2,Robin B. Harris and Ute M. Weisgerbe Cancer
Prevention and Control, Arizona Cancer Center, College of Medicine,
University of Arizona, Tucson, Arizona 85724 [I. A. H., R. B. H.], and
Unilever Health Institute Vlaardingen, 3130 AC Vlaardingen, the
Netherlands [U. M. W.]
Abstract
Differences in tea drinking habits are likely to vary by populations and
could contribute to the inconsistencies found between studies comparing
tea consumption and cancer risk. A population-based case-control study
was used to evaluate how usual tea consumption patterns of an older
population (n = 450) varied with history of
squamous cell carcinoma (SCC) of the skin. A detailed tea questionnaire
was developed to assess specific tea preparation methods and patterns
of drinking. In this southwestern United States population, black tea
was the predominant variety of tea consumed. We found no association
between the broad definition of any tea consumption and skin SCC.
However, the adjusted odds ratios (ORs) for hot and iced black tea
intake were 0.63 [95% confidence interval (CI), 0.36–1.10] and 1.02
(95% CI, 0.64–1.63), respectively. Controls were more likely to
report usually drinking strong hot tea (OR, 0.74; 95% CI, 0.53–1.03)
with increased brewing time (P for trend = 0.03).
Adjusting for brewing time, the association between skin SCC and hot
black tea consumption suggests a significantly lower risk in consumers
of hot tea compared to nonconsumers (OR, 0.33; 95% CI, 0.12–0.87).
This is one of the first studies to explore the relation between
different types of tea consumption and occurrence of human cancers. Our
results show that tea concentration (strength), brewing time, and
beverage temperature have major influences on the potential protective
effects of hot black tea in relation to skin SCC. Further studies with
increased sample sizes are needed to evaluate the interrelationships
between preparation techniques, tea type, and other life-style factors
Berberine inhibits growth, induces G1 arrest and apoptosis in human epidermoid carcinoma A431 cells by regulating Cdki–Cdk-cyclin cascade, disruption of mitochondrial membrane potential and cleavage of caspase 3 and PAR Sudheer K. Mantena1,Som D. Sharma1 andSantosh K. Katiyar1,2,3,*
Abstract Chemotherapeutic approach using non-toxic botanicals may be one of the strategies for the management of the skin cancers. Here we report that in vitro treatment of human epidermoid carcinoma A431 cells with berberine, a naturally occurring isoquinoline alkaloid, decreased cell viability (3–77%, P < 0.05–0.001) and induced cell death (3–51%, P < 0.01–0.001) in a dose (5–75 μM)- and time (12–72 h)-dependent manner, which was associated with an increase in G1 arrest. G0/G1 phase of the cell cycle is known to be controlled by cyclin dependent kinases (Cdk), cyclin kinase inhibitors (Cdki) and cyclins. Our western blot analysis showed that berberine-induced G1 cell cycle arrest was mediated through the increased expression of Cdki proteins (Cip1/p21 and Kip1/p27), a simultaneous decrease in Cdk2, Cdk4, Cdk6 and cyclins D1, D2 and E and enhanced binding of Cdki–Cdk. In additional studies, treatment of A431 cells with berberine (15–75 μM) for 72 h resulted in a significant dose-dependent increase in apoptosis (31–60%, P < 0.05–0.001) than non-berberine-treated control (11.7%), which was associated with an increased expression of pro-apoptotic protein Bax, decreased expression of anti-apoptotic proteins Bcl-2 and Bcl-xl, disruption of mitochondrial membrane potential, and activation of caspases 9, 3 and poly (ADP-ribose) polymerase. Pretreatment of A431 cells with the pan-caspase inhibitor (z-VAD-fmk) significantly blocked the berberine-induced apoptosis in A431 cells confirmed that berberine-induced apoptosis is mediated through activation of caspase 3-dependent pathway. Together, this study for the first time identified berberine as a chemotherapeutic agent against human epidermoid carcinoma A431 cells in vitro, further in vivo studies are required to determine whether berberine could be an effective chemotherapeutic agent for the management of non-melanoma skin cancers.
Introduction The risk of cancer is a growing health problem around the world particularly with the constantly rise in life expectancy, changes in environmental conditions, dietary habits and lifestyle. Among all the cancers, the incidence of non-melanoma skin cancers, including the squamous and basal cell carcinomas, represent the most common malignant neoplasms in humans, particularly in Caucasians. It has been estimated that ∼1.3 million new cases of skin cancers are diagnosed each year in the USA alone (1), which is equivalent to the incidence of malignancies in all other organs combined (2). According to current projections, one in five Americans will develop at least one non-melanoma skin cancer during their life-time. Thus cutaneous malignancies currently are a major burden on public health and healthcare expenditures. While not denying the importance of currently available sunscreens in the prevention of the risk of non-melanoma skin cancers, the use of sunscreens do not adequately protect the skin from the risk of cutaneous malignancies (3). Therefore, the development of effective chemopreventive or chemotherapeutic agents is required to address this issue.
There has been a considerable interest in the use of phytochemicals for the prevention of skin disorders including the risk of skin cancers. It has been noted that out of 121 prescription drugs in use for cancer treatment, 90 are derived from natural plant sources and ∼74% of these chemotherapeutic drugs were discovered by investigating a folklore claim (4,5). Berberine is an isoquinoline alkaloid present in the roots, rhizome and stem bark of a number of important medicinal plant species (e.g. Berberis aquifolium, Berberis vulgaris, Berberis aristata and Tinospora cordifolia etc.). The potential importance of berberine is indicated by its use in the Indian Ayurvedic (6), Unani and Chinese systems of medicine since time immemorial. Berberine possesses a wide range of biochemical and pharmacological activities, viz. antidiarrheal, antiarrhythmic and antitumor activities (7–10). Coptidis rhizoma, containing abundant berberine, is shown to inhibit the proliferation of esophageal cancer cells (11). Berberine inhibits cyclooxygenase-2 transcriptional activity in human colon cancer cells (10,12), and preliminary studies have shown that berberine sulfate inhibits tumor promoting activity of teleocidin in two-stage chemical carcinogenesis on mouse skin (13). Berberine also inhibits DNA topoisomerase I and II in biochemical system (14,15), and in fact, several classes of compounds that inhibit eukaryotic topoisomerase I or II have antitumor activity (16). Therefore, in an effort to develop an effective chemotherapeutic drug or agent for the prevention of non-melanoma skin cancers, we attempted for the first time to examine the chemotherapeutic effect of berberine on human epidermoid carcinoma A431 cells in in vitro system. We show that berberine inhibits the growth, proliferation and induces apoptosis in A431 cells. Our study also provides insight into the mechanism by which berberine induces apoptosis in these cells.
Source : Carcinogenesis (2006) 27 (10): 2018-2027. doi: 10.1093/carcin/bgl043 LINK TO FULL ARTICLE
Inhibitory effect of capsaicin on B16-F10 melanoma cell migration via the phosphatidylinositol 3-kinase/Akt/Rac1 signal pathway Dong-Hoon Shin,1 Ok-Hee Kim,2 Hye-Seung Jun,2 and Mi-Kyung Kang3
1Department of General Surgery, Kosin University College of Medicine, Busan 602-739, Korea.3Institute for Medical Science, Kosin University College of Medicine, Busan 602-739, Korea .2National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul 122-704, Korea.
Abstract Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), the major pungent ingredient of red pepper, has been reported to possess anti-carcinogenic and anti-mutagenic activities. In this study, the anti-migration activity of capsaicin on highly metastatic B16-F10 melanoma cells was investigated. Capsaicin significantly inhibited the migration of melanoma cells without showing obvious cellular cytotoxicity at low doses. This effect correlated with the down-regulation of phosphatidylinositol 3-kinase (PI3-K) and its downstream target, Akt. Although B16-F10 cell migration was increased by the PI3-K activator through the activation of Akt, these PI3-K activator-induced phenomena were attenuated by capsaicin. Moreover, capsaicin was found to significantly inhibit Rac1 activity in a pull-down assay. These results demonstrate that capsaicin inhibits the migration of B16-F10 cells through the inhibition of the PI3-K/Akt/Rac1 signal pathway. The present investigation suggests that capsaicin targets PI3-K/Akt/Rac1-mediated cellular events in B16-F10 melanoma cells. Consequently, capsaicin administration should be considered an effective approach for the suppression of invasion and metastasis in malignant melanoma chemotherapy.
Discussion Capsaicin is an active component of red peppers of the genus Capsicum (Cordell and Araujo, 1993). It has been reported to possess inhibitory effects on colon and gastric carcinogenesis (Jung et al., 2001; Kim et al., 2004), and was also found to inhibit carcinogeneisis in mouse skin (Park and Surh, 1997; Park et al., 1998). Recently, Mori et al. (2006) reported that capsaicin could be effective against prostate cancer by inhibiting androgen-independent growth. Furthermore, capsaicin had strong apoptotic activity in B16-F10 cells via the down-regulation of Bcl-2 (Jun et al., 2007). In the present study, the anti-migratory properties of capsaicin in highly metastatic B16-F10 melanoma cells were investigated. Capsaicin efficiently suppressed the migration of B16-F10 cells without obvious cellular cytotoxicity (Figure 1). These results suggest that capsaicin could have an effective role in the management of melanoma cancer patients.PI3-K is considered to be one of the main intracellular factors responsible for the transmission of cell migration signals (Krasilnikov, 2000). In addition, Akt, one of the major downstream targets of PI3-K, promotes cell motility and migration in tumor cells (Morales-Ruiz et al., 2000). It has been indicated that the PI3-K/Akt signaling pathway is required for the invasion and metastasis of cancer cells. Thus, we hypothesized that the inhibition of the PI3-K/Akt pathway was the underlying mechanism responsible for the inhibitory effect of capsaicin on the migration of B16-F10 cells. This hypothesis is supported by the observation that capsaicin suppresses the phosphorylation of Akt (Figure 2). In addition, capsaicin inhibited migration and Akt phosphorylation in B16-F10 cells; these processes are activated by a PI3-K activator (Figure 3). These results demonstrate that capsaicin is an inhibitor of the PI3-K/Akt signaling pathway in B16-F10 melanoma cells. Our findings are basically consistent with previous reports on the inhibition of the PI3-K pathway and the suppression of cell migration by other chemopreventive agents such as red wine polyphenols (Iijima et al., 2002), sulindac sulfide, and caffeic acid phenethyl ester (Shigeoka et al., 2003).Rac1 was reported to act as a downstream effector of PI3-K in several growth factor-stimulated pathways (Higuchi et al., 2001), and to induce invasion and metastasis in cancer cells (Price and Collard, 2001). Conversely, several studies suggest that Rac1 acts upstream of PI3-K to increase cellular motility and invasiveness in T47D mammary carcinoma cells and H-Ras-activated MCF-10A breast epithelial cells (Keely et al., 1997; Shin et al., 2005). Rac1 activation also played a critical role in the migration of cancer cells (Stem et al., 1998). Although we did not address the signaling pathways between PI3-K and Rac1, our results showing inhibition of Rac1 activation following capsaicin treatment in B16-F10 cells are in line with these observations (Figure 4). This inhibition might lead to the inactivation of Akt and may, in turn, affect the migration of B16-F10 cells. These results suggest that, in addition to its inhibitory effect on the PI3-K/Akt signaling pathway, capsaicin might also inhibit cell migration by down-regulating Rac1. However, a previous study reported that activation of PI3-K/Rac1 signaling inhibits cell migration in human melanoma cells (Kallergi et al., 2007). Therefore, the functions of Rac1 on migration are at least in part cell type- and cell substrate-dependent. However, further studies are needed to investigate whether capsaicin-induced Rac1 activation is PI3-K-dependent in B16-F10 melanoma cells.It is well known that capsaicin is a specific agonist of the transient receptor potential vanilloid 1 (TRPV1) family of ion channels (Caterina et al., 1997). Several reports have indicated that the anti-cancer effects of capsaicin are not to activate TRPV1 (Raisinghani et al., 2005), but to inhibit plasma membrane NADH oxidase (Morre et al., 1995). Moreover, alternative anti-cancer mechanisms of capsaicin have been associated with the production of reactive oxygen species (Qiao et al., 2005) and the reduction of TNF-α (Park et al., 2004). In a review, Surh (2002) indicated that capsaicin could mediate suicide in human skin cancer cells via the excessive generation of reactive oxygen species (ROS), according to the inhibition of mitochondrial and plasma membrane electron transport systems. Therefore, further study is required to determine whether the inhibition of migration by capsaicin is due to the function of capsaicin-sensitive TRPV1 channels and the availability and efficiency of antioxidant capacity.Collectively, we found that non-toxic levels of capsaicin could efficiently suppress the migration of B16-F10 melanoma cells; this suppression is achieved through the inhibition of the PI3-K/Akt signal pathway and Rac1 activity. Thus, the present study provides novel insights into the molecular mechanisms of capsaicin. Furthermore, anti-migration of highly metastatic B16-F10 melanoma cells by capsaicin can be considered an effective approach for the suppression of cancer invasion and metastasis.
Multi-targeted Therapy of Cancer by Omega-3 Fatty Acids
Isabelle M. Berquin1,2, Iris J. Edwards2, and Yong Q. Chen1* 1Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina. 2Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) are essential fatty acids necessary for human health. Currently, the Western diet contains a disproportionally high amount of n-6 PUFAs and low amount of n-3 PUFAs, and the resulting high n-6/n-3 ratio is thought to contribute to cardiovascular disease, inflammation, and cancer. Studies in human populations have linked high consumption of fish or fish oil to reduced risk of colon, prostate and breast cancer, although other studies failed to find a significant association. Nonetheless, the available epidemiological evidence, combined with the demonstrated effects of n-3 PUFAs on cancer in animal and cell culture models, has motivated the development of clinical interventions using n-3 PUFAs in the prevention and treatment of cancer, as well as for nutritional support of cancer patients to reduce weight loss and modulate the immune system. In this review, we discuss the rationale for using long-chain n-3 PUFAs in cancer prevention and treatment and the challenges that such approaches pose in the design of clinical trials.
Source Cancer Lett. 2008 October 8; 269(2): 363–377. doi:10.1016/j.canlet.2008.03.044 LINK TO FULL ARTICLE
The Cinnamon-derived Michael Acceptor Cinnamic Aldehyde Impairs Melanoma Cell Proliferation, Invasiveness, and Tumor Growth
Christopher M. Cabello, Warner B. Bair, 3rd, Sarah D. Lamore, Stephanie Ley, Alexandra S. Bause, Sara Azimian, and Georg T. Wondrak*Department of Pharmacology and Toxicology, College of Pharmacy, Arizona Cancer Center, University of Arizona, Tucson, AZ, USA *Address correspondence to: Georg T. Wondrak, Ph.D. University of Arizona, Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, AZ 85724 USA
Abstract Redox dysregulation in cancer cells represents a chemical vulnerability that can be targeted by prooxidant redox intervention. Dietary constituents that contain an electrophilic Michael acceptor pharmacophore may therefore display promising chemopreventive and chemotherapeutic anti-cancer activity. Here, we demonstrate that the cinnamon-derived dietary Michael acceptor trans-cinnamic aldehyde (CA) impairs melanoma cell proliferation and tumor growth. Feasibility of therapeutic intervention using high doses of CA (120 mg/kg, p.o., q.d., 10 days) was demonstrated in a human A375 melanoma SCID-mouse xenograft model. Low micromolar concentrations (IC50 < 10 μM) of CA, but not closely related CA-derivatives devoid of Michael acceptor activity, suppressed proliferation of human metastatic melanoma cell lines (A375, G361, LOX) with G1 cell cycle arrest, elevated intracellular ROS, and impaired invasiveness. Expression array analysis revealed that CA induced an oxidative stress response in A375 cells, up-regulating heme oxygenase-1 (HMOX1), sulfiredoxin 1 homolog (SRXN1), thioredoxin reductase 1 (TXNRD1), and other genes including the cell cycle regulator and stress-responsive tumor suppressor gene cyclin-dependent kinase inhibitor 1A (CDKN1A), a key mediator of G1 phase arrest. CA, but not Michael-inactive derivatives, inhibited NFκB transcriptional activity and TNFα-induced IL-8 production in A375 cells. These findings support a previously unrecognized role of CA as a dietary Michael acceptor with potential anticancer activity.
Source : National Institute of Health LINK TO FULL ARTICLE Cinnamon extract induces tumor cell death through inhibition of NFκB and AP1
1 School of Life Sciences and Immune Synapse Research Center, Gwangju Institute of Science and Technology (GIST), 1 Oryong-dong, Puk-ku, Gwangju 500-712, Republic of Korea 2 Korea Institute of Oriental Medicine, Daejeon 305-811, Republic of Korea 3 Global leader program, Bugil Academy, Cheonan, Gyeonggido 330-941, Republic of Korea 4 Chosun University School of Medicine, Gwangju 501-759, Republic of Korea
Background Cinnamomum cassia bark is the outer skin of an evergreen tall tree belonging to the family Lauraceae containing several active components such as essential oils (cinnamic aldehyde and cinnamyl aldehyde), tannin, mucus and carbohydrate. They have various biological functions including anti-oxidant, anti-microbial, anti-inflammation, anti-diabetic and anti-tumor activity. Previously, we have reported that anti-cancer effect of cinnamon extracts is associated with modulation of angiogenesis and effector function of CD8+ T cells. In this study, we further identified that anti-tumor effect of cinnamon extracts is also link with enhanced pro-apoptotic activity by inhibiting the activities NFκB and AP1 in mouse melanoma model.
Methods Water soluble cinnamon extract was obtained and quality of cinnamon extract was evaluated by HPLC (High Performance Liquid Chromatography) analysis. In this study, we tested anti-tumor activity and elucidated action mechanism of cinnamon extract using various types of tumor cell lines including lymphoma, melanoma, cervix cancer and colorectal cancer in vitro and in vivo mouse melanoma model.
Results Cinnamon extract strongly inhibited tumor cell proliferation in vitro and induced active cell death of tumor cells by up-regulating pro-apoptotic molecules while inhibiting NFκB and AP1 activity and their target genes such as Bcl-2, BcL-xL and survivin. Oral administration of cinnamon extract in melanoma transplantation model significantly inhibited tumor growth with the same mechanism of action observed in vitro.
Conclusion Our study suggests that anti-tumor effect of cinnamon extracts is directly linked with enhanced pro-apoptotic activity and inhibition of NFκB and AP1 activities and their target genes in vitro and in vivo mouse melanoma model. Hence, further elucidation of active components of cinnamon extract could lead to development of potent anti-tumor agent or complementary and alternative medicine for the treatment of diverse cancers.
SOURCE : BMC Cancer 2010, 10:392doi:10.1186/1471-2407-10-392 LINK TO FULL ARTICLE
Inhibitory Effects of Orally Administered Green Tea, Black Tea, and Caffeine on Skin Carcinogenesis in Mice Previously Treated with Ultraviolet B Light (High-Risk Mice) Relationship to Decreased Tissue Fat
+ Author Affiliations Laboratory for Cancer Research, Department of Chemical Biology, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854-8020 [Y-P. L., Y-R. L., M-T. H., C. S. Y., A. H. C.]; University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901 [Y. L., W. J. S.]; and The Cancer Institute of New Jersey, New Brunswick, New Jersey 08901 [Y. L., W. J. S., M-T. H., C. S. Y., A. H. C.]
Abstract Treatment of SKH-1 hairless mice with ultraviolet B light (UVB; 30 mJ/cm2) twice a week for 22 weeks resulted in tumor-free animals with a high risk of developing malignant and nonmalignant skin tumors during the next several months in the absence of additional UVB treatment (high-risk mice). Oral administration of green tea or black tea (6 mg tea solids/ml) to UVB-pretreated high-risk SKH-1 mice for 23 weeks after stopping UVB treatment decreased the number of tumors/mouse, decreased the size of the parametrial fat pads, and decreased the thickness of the dermal fat layer away from tumors and directly under tumors. Administration of the decaffeinated teas had little or no effect on these parameters, and adding caffeine (equivalent to the amount in the regular teas) to the decaffeinated teas restored their inhibitory effects. Administration of caffeine alone also decreased the number of tumors/mouse, the size of the parametrial fat pads, and the thickness of the dermal fat layer away from tumors and under tumors. Using data from individual mice and linear regression and correlation analysis, we found a highly significant positive correlation between the thickness of the dermal fat layer away from tumors and the number of tumors/mouse (r = 0.34; P = 0.0001), but the correlation between average tumor size/mouse and the thickness of the dermal fat layer away from tumors was weak (r = 0.16; P = 0.034). The results suggested that p.o. administered tea or caffeine may have decreased tumor multiplicity in part by decreasing fat levels in the dermis. Additional analysis revealed that oral administration of caffeinated beverages (green tea, black tea, decaffeinated green tea plus caffeine, decaffeinated black tea plus caffeine, or caffeine alone) decreased the thickness of the dermal fat layer under large tumors to a much greater extent than under small tumors. This is the first demonstration of a close association between inhibition of carcinogenesis and the lowering of tissue fat levels by a chemopreventive agent.
Topical applications of caffeine or (−)-epigallocatechin gallate (EGCG) inhibit carcinogenesis and selectively increase apoptosis in UVB-induced skin tumors in mice
Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, State University of New Jersey, Piscataway, NJ 08854-8020 Contributed by Allan H. Conney
Abstract SKH-1 hairless mice were irradiated with ultraviolet B (UVB) twice weekly for 20 weeks. These tumor-free mice, which had a high risk of developing skin tumors during the next several months, were then treated topically with caffeine (6.2 μmol) or (−)-epigallocatechin gallate (EGCG; 6.5 μmol) once a day 5 days a week for 18 weeks in the absence of further treatment with UVB. Topical applications of caffeine to these mice decreased the number of nonmalignant and malignant skin tumors per mouse by 44% and 72%, respectively. Topical applications of EGCG decreased the number of nonmalignant and malignant tumors per mouse by 55% and 66%, respectively. Immunohistochemical analysis showed that topical applications of caffeine or EGCG increased apoptosis as measured by the number of caspase 3-positive cells in nonmalignant skin tumors by 87% or 72%, respectively, and in squamous cell carcinomas by 92% or 56%, respectively, but there was no effect on apoptosis in nontumor areas of the epidermis. Topical applications of caffeine or EGCG had a small inhibitory effect on proliferation in nonmalignant tumors as measured by BrdUrd labeling (16–22%), and there was also a similar, but nonsignificant, inhibitory effect on proliferation in malignant tumors. The results suggest a need for further studies to determine whether topical applications of caffeine or EGCG can inhibit sunlight-induced skin cancer in humans.
Source : Proceedings of the National Academy of Sciences of The United States of America LINK TO FULL ARTICLE
Abstract Background The alkylating agent Dacarbazine (DTIC) has been used in the treatment of melanoma for decades, but when used as a monotherapy for cancer only moderate response rates are achieved. Recently, the clinical use of Temozolomide (TMZ) has become the more commonly used analog of DTIC-related oral agents because of its greater bioavailability and ability to cross the blood brain barrier. The response rates achieved by TMZ are also unsatisfactory, so there is great interest in identifying compounds that could be used in combination therapy. We have previously demonstrated that the bioflavonoid quercetin (Qct) promoted a p53-mediated response and sensitized melanoma to DTIC. Here we demonstrate that Qct also sensitizes cells to TMZ and propose a mechanism that involves the modulation of a truncated p53 family member, ΔNp73.
Methods DB-1 melanoma (p53 wildtype), and SK Mel 28 (p53 mutant) cell lines were treated with TMZ (400 μM) for 48 hrs followed by Qct (75 μM) for 24 hrs. Cell death was determined by Annexin V-FITC staining and immunocytochemical analysis was carried out to determine protein translocation.
Results After treatment with TMZ, DB-1 cells demonstrated increased phosphorylation of Ataxia telangiectasia mutated (ATM) and p53. However, the cells were resistant to TMZ-induced apoptosis and the resistance was associated with an increase in nuclear localization of ΔNp73. Qct treatment in combination with TMZ abolished drug insensitivity and caused a more than additive induction of apoptosis compared to either treatment alone. Treatment with Qct, caused redistribution of ΔNp73 into the cytoplasm and nucleus, which has been associated with increased p53 transcriptional activity. Knockdown of ΔNp73 restored PARP cleavage in the TMZ treated cells, confirming its anti-apoptotic role. The response to treatment was predominantly p53 mediated as the p53 mutant SK Mel 28 cells showed no significant enhancement of apoptosis.
Conclusion This study demonstrates that Qct can sensitize cells to TMZ and that the mechanisms of sensitization involve modulation of p53 family members.
Source: BMC Cancer 2010, 10:282doi:10.1186/1471-2407-10-282 LINK TO SOURCE
The chemopreventive flavonoidapigenin induces G2/M arrest in keratinocytes
Denise M. Lepley 1, Boyong Li 1, Diane F. Birt 1 and Jill C. Pelling 2 3 1University of Nebraska Medical Center, Eppley Institute for Cancer Research Omaha, NE 68198 2University of Kansas Medical Center, Department of Pathology and Laboratory Medicine Kansas City, KS 66160, USA
Abstract Apigenin is a plant flavonoid which has been shown to significantly inhibit UV-induced mouse skin tumorigenesis when applied topically,and may represent an alternative sunscreen agent in humans.We have investigated the molecular mechanism(s) by which apigeni inhibits skin tumorigenesis. Initial studies examined the effects of apigenin on the cell cycle. DNA flow cytometric analysisindicated that culturing cells for 24 h in medium containing apigenin induced a G2/M arrest in two mouse skin derived cell lines, C50 and 308, as well as in human HL-60 cells. The G2/Marrest was fully reversible after an additional 24 h in mediumwithout apigenin. We investigated the effects of apigenin oncyclin B1 and p34cdc2, since cyclin B1/p34cdc2 complexes regulateG2/M progression. Western blot and immune complex kinase assay using whole cell lysates from 308 and C50 cells treated for24 h with 0–70 µM doses of apigenin demonstrated that apigenin treatment did not change the steady-state level of p34cdc2 protein, but did inhibit p34cdc2 H1 kinase activity in 308 cells. Western blot analysis showed that apigenin treatment of C50 cells and 308 cells inhibited the accumulation of cyclinB1 protein in a dose-dependent manner. The apigenin levels detected in cultured keratinocytes were relevant to those detected in epidermal cells of Sencar mice treated with tumor inhibitory doses of apigenin. In conclusion, we present evidence that apigenin induces a reversible G2/M arrest in cultured keratinocytes,the mechanism of which is in part due to inhibition of the mitotickinase activity of p34cdc2, and perturbation of cyclin B1 levels.
Department of Oncology and Neurosciences, G. D'Annunzio University, Chieti, Italy. [email protected]
Flavonoids are a class of polyphenolic compounds widely distributed in the plant kingdom, which display a variety of biological activities, including chemoprevention and tumor growth inhibition. Our aim was to investigate the effects of several polyphenols on the growth and metastatic potential of B16-BL6 melanoma cells in vivo. Intraperitoneal administration of quercetin, apigenin, (-)-epigallocathechin-3-gallate (EGCG), resveratrol, and the anti-estrogen tamoxifen, at the time of i.m. injection of B16-BL6 cells into syngeneic mice, resulted in a significant, dose-dependent delay of tumor growth, without toxicity. The relative descending order of potency was EGCG > apigenin = quercetin = tamoxifen > resveratrol > control. Furthermore, polyphenols significantly potentiated the inhibitory effect of a non-toxic dose of cisplatin. When tested for the ability to inhibit lung colonization, quercetin, apigenin, and tamoxifen (but not EGCG or resveratrol) significantly decreased the number of B16-BL6 colonies in the lungs in a dose-dependent manner, with quercetin and apigenin being more effective than tamoxifen. Interestingly, quercetin, apigenin, and tamoxifen (but not EGCG or resveratrol) significantly decreased the invasion of B16-BL6 cells in vitro, with quercetin and apigenin being more effective than tamoxifen. This suggests that anti-invasive activity is one of the mechanisms underlying inhibition of lung colonization by quercetin and apigenin. In conclusion, quercetin and apigenin inhibit melanoma growth and invasive and metastatic potential; therefore, they may constitute a valuable tool in the combination therapy of metastatic melanoma.
Serum 25-Hydroxyvitamin D3 Levels Are Associated With Breslow Thickness at Presentation and Survival From Melanoma
Julia A. Newton-Bishop,* Samantha Beswick, Juliette Randerson-Moor, Yu-Mei Chang, Paul Affleck, Faye Elliott, May Chan, Susan Leake, Birute Karpavicius, Sue Haynes, Kairen Kukalizch, Linda Whitaker, Sharon Jackson, Edwina Gerry, Clarissa Nolan, Chandra Bertram, Jerry Marsden, David E. Elder, Jennifer H. Barrett, and D. Timothy Bishop
From the Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds; Department of Dermatology, University Hospital Birmingham National Health Service Foundation Trust, Birmingham, United Kingdom; and Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA.
Purpose: A cohort study was carried out to test the hypothesis that higher vitamin D levels reduce the risk of relapse from melanoma.
Methods: A pilot retrospective study of 271 patients with melanoma suggested that vitamin D may protect against recurrence of melanoma. We tested these findings in a survival analysis in a cohort of 872 patients recruited to the Leeds Melanoma Cohort (median follow-up, 4.7 years).
Results: In the retrospective study, self-reports of taking vitamin D supplements were nonsignificantly correlated with a reduced risk of melanoma relapse (odds ratio= 0.6; 95% CI, 0.4 to 1.1; P = .09). Nonrelapsers had highermean 25-hydroxyvitamin D3 levels than relapsers (49 v 46 nmol/L;P = .3; not statistically significant). In the cohort (prospective)study, higher 25-hydroxyvitamin D3 levels were associated withlower Breslow thickness at diagnosis (P = .002) and were independently protective of relapse and death: the hazard ratio for relapse-freesurvival (RFS) was 0.79 (95% CI, 0.64 to 0.96; P = .01) fora 20 nmol/L increase in serum level. There was evidence of interaction between the vitamin D receptor (VDR) BsmI genotype and serum25-hydroxyvitamin D3 levels on RFS.
Conclusion: Results from the retrospective study were consistent with a role for vitamin D in melanoma outcome. The cohort study tests this hypothesis,providing evidence that higher 25-hydroxyvitamin D3 levels,at diagnosis, are associated with both thinner tumors and better survival from melanoma, independent of Breslow thickness. Patients with melanoma, and those at high risk of melanoma, should seek to ensure vitamin D sufficiency. Additional studies are needed to establish optimal serum levels for patients with melanoma.
Inhibition of Tumor Promotion in SENCAR Mouse Skin by Ethanol Extract ofZingiber officinale Rhizome1
Santosh K. Katiyar, Rajesh Agarwal, and Hasan MUkhtar
Depara@mentof Dermatology, Skin Diseases Research Center, University Hospitals of Cleveland, Case Western Reserve University, Cleveland. Ohio 44106
Abstract
There is considerable emphasis on Identifying potential chemopreventive agents present in food consumed by the human population. Ginger rhizome (Zingiber officinale), known commonly as ginger, Is consumed worldwide in cookeries as a spice and a flavoring agent. In prior in vitro studies, it has been shown that the water or organic solvent extract of ginger possesses antioxidative and antlinflammatory properties. In this study, we evaluated whether ethanol extract of ginger (GE) possesses anti-tumor.promoting effects In a mouse skin tumorigenesis model. Because skin tumor promoters induced epidermal ornithine decarboxylase (ODC), cyclooxygenase, and lipoxygenase activities, and edema and hyperplasia are conventionally used markers of skin tumor promotion, first,we assessed the effect of GE on these parameters. Preapplication of GE onto the skin of SENCAR mice resulted in significant inhibition of 12-0-tetradecanoylphorbol-13-acetate (TPA)-caused induction of epidermal ODC, cyclooxygenase, and lipoxygenase activities and ODC mRNA expression In a dose-dependent manner. Preapplication of GE to mouse skin also afforded significant inhibition of TPA-caused epidermal edema (56%) and hyperplasia (44%). In long-term tumor studies, topical application of GE 30 mm prior to that of each TPA application to 7,12-dimethylbenz(a)anthracene-initiated SENCAR mice resulted in a highly significant protection against skin tumor incidence and Its subsequent multiplicity. The animals pretreated with GE showed substantially lower tumor body burdens compared with non-GE-treated controls. The results of our study,for the first time,provide clear evidence that GE possesses anti-skin tumor-promoting effects, and that the mechanism ofsuch effects may involve inhibition of tumor promoter-caused cellular, biochemical, and molecular changes in mouse skin.
Differential Growth Suppression of Human Melanoma Cells by Tea (Camellia sinensis) Epicatechins (ECG, EGC and EGCG)
Mepur H. Ravindranath, Vaishali Ramasamy, Songeun Moon, Carlos Ruiz and Sakunthala Muthugounder
Department of Glycoimmunotherapy, John Wayne Cancer Institute, Santa Monica, CA 90404, USA We previously reported that catechins of green tea have different antiproliferative effects on celllines derived from gender-dependent cancers; epicatechin 3-gallate (ECG) had the strongest inhibitory effect. In the present study, we examined the effects of epigallocatechin (EGC),epicatechin-gallate (ECG) and EGC 3-gallate (EGCG) on the viability, density, doubling time and cycle number of cell lines derived from melanoma metastasized to lymph nodes (MB-1133and SE-0154) or distant organs (CH-0356, JK-0346, SA-1171, GE-0208, NS-1176 and LF-0023). These catechins have been documented to have no growth suppressive or apoptotic effects on normal melanocytes (Nihal et al., Int J Cancer 2005;114:513–21). EGCG (50 mM)showed greater inhibitory potency than EGC (50 mM) in SE-0154, NS-1176, GE-0208 and LF-0023 cell lines but the two catechins produced similar inhibitory effects in CH-0356,JK-0346 and SA-1171 cell lines. The IC50 (50% inhibitory concentration) was lower for EGC than EGCG in MB-1133 and CH-0356 cells, higher for EGC than EGCG in GE-0208 cells andcomparable (11–12 mM) for both the catechins in LF-0023 cells. When compared with EGC, the cytotoxic effect (% dead cell counts) and the suppression of the growth (change in cell number) of all melanoma cell lines tested were pronounced with EGCG. This investigation validates the hypothesis that anticancer action of the various catechins may vary with the type of malignancy and provides a model for tumor cell heterogeneity based on susceptibility and resistance of tumor cells to different green tea catechins. Therefore, this information is critical for undertaking chemopreventive or chemotherapeutic trials against melanoma and gender-based cancers
Comparison of Radical Scavenging Activity, Cytotoxic Effects and Apoptosis Induction in Human Melanoma Cells by Taiwanese Propolis from Different Sources
Chia-Nan Chen1, Meng-Shih Weng1, Chia-Li Wu2 and Jen-Kun Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Section 1 Jen-Ai Road, Taipei 100, Taiwan, and 2Department of Chemistry, Tamkang University Tamsui 251, Taiwan
Propolis is a sticky substance that is collected from plantsby honeybees. We previously demonstrated that propolins A, B,C, D, E and F, isolated from Taiwanese propolis (TP), couldeffectively induce human melanoma cell apoptosis and were strongantioxidant agents. In this study, we evaluated TP for freeradical scavenging activity by DPPH (1,2-diphenyl-2-picrylhydrazyl).The phenolic concentrations were quantified by the Folin–Ciocalteumethod. The apoptosis trigger activity in human melanoma cellswas evaluated. TP contained a higher level of phenolic compoundsand showed strong capability to scavenge free radicals. Additionally,TP1g, TP3, TP4 and TP7 exhibited a cytotoxic effect on humanmelanoma cells, with an IC50 of 2.3, 2.0, 3.3 and 3.3 µg/ml,respectively. Flow cytometric analysis for DNA fragmentationindicated that TP1g, TP2, TP3 and TP7 could induce apoptosisin human melanoma cells and there is a marked loss of cellsfrom the G2/M phase of the cell cycle. To address the mechanismof the apoptosis effect of TP, we evaluated its effects on inductionof apoptosis-related proteins in human melanoma cells. The levelsof procaspase-3 and PARP [poly(ADP-ribose) polymerase] weremarkedly decreased. Furthermore, propolins A, B, C, D, E andF in TP were determined using HPLC. The results indicate thatTP is a rich source of these compounds. The findings suggestthat TP induces apoptosis in human melanoma cells due to itshigh level of propolins.
Inhibitory effects of caffeic acid phenethyl ester (CAPE) on 12-0-tetradecanoylphorbol-13-acetate-induced tumor promotion in mouse skin and the synthesis of DNA, RNA and protein in HeLa cells Mou-Tuan Huang, Wei Ma, Patricia Yen, Jian-Guo Xie, Jingkang Han1, Krystyna Frenkel1, Dezider Grunberger, and Allan H-Conney
Laboratory for Cancer Research, Department of Chemical Biology, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08855-0789, 'Department of Environmental Medicine, New York University Medical Center, New York, NY 10016-6451 and institute of Cancer Research, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
Topical application of caffeic acid phenethyl ester (CAPE), a constituent of the propolis of honeybee hives, to the backs of CD-I mice previously initiated with 7,12- dimethylbenz[<i]anthracene (DMBA) inhibited 12-0-tetradecanoylphorbol-13-acetate (TPA)-induced tumor promotion and the formation of 5-hydroxymethyl-2'-deoxyuridine (HMdU) in epidermal DNA. Topical application of 5 nmol TPA twice weekly for 20 weeks to mice previously initiated with 200 nmol of DMBA resulted in 18.8 skin papillomas per mouse. Topical application of 1, 10, 100 or 3000 nmol of CAPE together with 5 nmol of TPA twice a week for 20 weeks inhibited the number of skin papillomas per mouse by 24, 30, 45 or 70%, respectively, and tumor size per mouse was decreased by 42, 66, 53 or 74%, respectively.Topical application of 5 nmol of TPA twice weekly for 20 weeks to mice previously initiated with DMBA produced an average of 12.6 HMdU residues per 104 normal bases in epidermal DNA. Topical application of 1, 10, 100 or 3000 nmol of CAPE with 5 nmol of TPA twice weekly for 20 weeks to DMBA-initiated mice decreased the level of HMdU in epidermal DNA by 40-93%. The in vitro addition of 1.25, 2.5, 5, 10 or 20 jiM CAPE to cultured HeLa cells inhibited the synthesis of DNA by 32, 44, 66, 79 or 95%, respectively, the synthesis of RNA was inhibited by 39, 43,58, 64 or 75%, respectively, and the synthesis of protein was inhibited by 29, 30, 37, 32 or 47%, respectively. The results indicate a potent inhibitory effect of CAPE on TPAinduced tumor promotion and TPA-induced formation of HMdU in DNA of mouse skin as well as an inhibitory effect of CAPE on the synthesis of DNA, RNA and protein in cultured HeLa cells.
Stimulation of lymphocyte anti-melanoma activity by co-cultured macrophages activated by complex homeopathic medication
Fernando SF Guimarães, Ana PR Abud, Simone M Oliveira, Carolina C Oliveira, Beatriz César, Lucas F Andrade, Lucélia Donatti, Juarez Gabardo, Edvaldo S Trindade, and Dorly F Buchi
Departamento de Biologia Celular, Laboratório de Pesquisa em Células Inflamatórias e Neoplásicas, Universidade Federal do Paraná (UFPR), Curitiba – PR, Brazil Abstract
BackgroundMelanoma is the most aggressive form of skin cancer, and the most rapidly expanding cancer in terms of worldwide incidence. Chemotherapeutic approaches to treat melanoma have been uniformly disappointing. A Brazilian complex homeopathic medication (CHM), used as an immune modulator, has been recommended for patients with depressed immune systems. Previous studies in mice have demonstrated that the CHM activates macrophages, induces an increase in the number of leukocytes and improves the murine response against Sarcoma-180
Conclusion Co-culture of macrophages with lymphocytes in the presence of the CHM enhanced the anti-cancer performance of lymphocytes against a very aggressive lineage of melanoma cells. These results suggest that non-toxic therapies using CHMs are a promising alternative approach to the treatment of melanomas. In addition, they are attractive combination-therapy candidates, which may enhance the efficacy of conventional medicines by improving the immune response against tumor cells.