Dietary Flavonoids Flavonoids are natural occurring polyphenolic compounds that are widely distributed in the plant kingdom, displaying a wide range of pharmacologic properties
Rutin attenuates intestinal toxicity induced by Methotrexate linked with anti-oxidative and anti-inflammatory effects
Raju Gautam,
Manjari Singh,
Swetlana Gautam,
Jitendra Kumar Rawat,
Shubhini A Saraf and
Gaurav Kaithwas
Abstract Background Methotrexate (MTX) is recognized as an anti-metabolite in cancer chemotherapy and is associated with various toxicities assigned to inflammation and oxidative stress. Rutin has been reported to have significant anti-inflammatory, antioxidant along with antiulcer properties. The present study was undertaken to corroborate the effect of rutin against MTX induced intestinal toxicity in experimental animals.
Method Six groups of rats (n = 6) were dosed with normal saline (3 ml/kg,i.p.); MTX (2.5 mg/kg,i.p.); rutin (50 and 100 mg/kg,i.p.); rutin + MTX (50 mg/kg + 2.5 mg/kg,i.p.); rutin + MTX (100 mg/kg + 2.5 mg/kg,i.p.) for seven consecutive days and sacrificed on eighth day. The intestinal contents were scrutinized physiologically (pH, total acidity, free acidity, CMDI), biochemically (TBARS, protein carbonyl, SOD, catalase and GSH) and for immunoregulatory cytokines (IL-2, IL-4 and IL-10).
Results and Discussion The administration of rutin demonstrated significant protection against intestinal lesions damaged by MTX. The treatment with rutin elicited noticeable inhibition of free acidity (26.20 %), total acidity (22.05 %) and CMDI (1.16 %) in the experimental animals similar to control. In MTX treated toxic group, the levels of oxidative markers and immunoregulatory cytokines significantly increased in comparison to control, which was subsequently restored after rutin treatment. Rutin also demonstrated 75.63, 81.00 and 80.43 % inhibition of cyclooxygenase-1 and 2, and 15-lipoxygenase respectively.
Conclusion The positive modulation of MTX toxicity could be attributed to the free radical scavenging and anti-inflammatory (dual inhibition of arachidonic acid pathways) potential of rutin.
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 rich foods Parsley, thyme, celery, hot peppers, chamomile tea,
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 [30]. 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,
Dietary Flavonoid Intake and Breast Cancer Risk among Women on Long Island
Brian N. Fink1, Susan E. Steck2, Mary S. Wolff3, Julie A. Britton3, Geoffrey C. Kabat4, Mia M. Gaudet1, Page E. Abrahamson1, Paula Bell1, Jane C. Schroeder1, Susan L. Teitelbaum3, Alfred I. Neugut5,6, and Marilie D. Gammon1
1 Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC. 2 Department of Nutrition, School of Public Health, University of North Carolina, Chapel Hill, NC. 3 Department of Community and Preventive Medicine, Mt. Sinai School of Medicine, New York, NY. 4 Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY. 5 Department of Epidemiology, Joseph L. Mailman School of Public Health, Columbia University, New York, NY. 6 Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY.
Flavonoids are found in a variety of foods and have anticarcinogenic properties in experimental models. Few epidemiologic studies have examined whether flavonoid intake is associated with breast cancer in humans. In this study, the authors investigated whether dietary flavonoid intake was associated with reduced risk of breast cancer in a population-based sample of US women. They conducted a case-control study among women who resided in Nassau and Suffolk counties on Long Island, New York. Cases and controls were interviewed about known and suspected risk factors and asked to complete a food frequency questionnaire regarding their average intake in the prior 12 months. A total of 1,434 breast cancer cases and 1,440 controls provided adequate responses. A decrease in breast cancer risk was associated with flavonoid intake; the decrease was most pronounced among postmenopausal women for flavonols (odds ratio (OR) ¼ 0.54, 95% confidence interval (CI): 0.40, 0.73), flavones (OR ¼0.61, 95% CI: 0.45, 0.83), flavan-3-ols (OR ¼ 0.74, 95% CI: 0.55, 0.99), and lignans (OR ¼ 0.69, 95% CI: 0.51,0.94).
The authors conclude that intake of flavonols, flavones, flavan-3-ols, and lignans is associated with reduced risk of incident postmenopausal breast cancer among Long Island women. These results suggest that US women can consume sufficient levels of flavonoids to benefit from their potential chemopreventive effects
Flavonoids - found in a variety of foods.. The most important dietary sources are fruits, tea and soybean. Green and black tea contains about 25% percent flavonoids. Other important sources of flavonoids are apple (quercetin), citrus fruits (rutin and hesperidin), Source: American Journal of Epidemiology Advance Access published December 11, 2006 LINK TO FULL ARTICLE
Apigenin is a flavonoid, a citrus bioflavonoid. Apigenin is found in high amounts in several herbs - chamomile, peppermint, lemon balm, thyme, parsley, , Horsetail, perilla, yarrow, vervain. The flavonoid apigenin can also be found in a variety of foods including apples, beans, broccoli, celery, cherries, grapes, leeks, onions, parsley and tomatoes, as well as plant-derived beverages like tea and wine.
Inhibition of proteasome activity by the dietary flavonoid apigenin is associated with growth inhibition in cultured breast cancer cells and xenografts
Di Chen,1 Kristin R Landis-Piwowar,1 Marina S Chen,1 and Q Ping Dou1
1The Prevention Program, Barbara Ann Karmanos Cancer Institute and Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201-2013, USA
Introduction Proteasome inhibition is an attractive approach to anticancer therapy and may have relevancy in breast cancer treatment. Natural products, such as dietary flavonoids, have been suggested as natural proteasome inhibitors with potential use for cancer prevention and therapeutics. We previously reported that apigenin, a flavonoid widely distributed in many fruits and vegetables, can inhibit proteasome activity and can induce apoptosis in cultured leukemia Jurkat T cells. Whether apigenin has proteasome-inhibitory activity in the highly metastatic human breast MDA-MB-231 cells and xenografts, however, is unknown.
Methods MDA-MB-231 breast cancer cell cultures and xenografts were treated with apigenin, followed by measurement of reduced cellular viability/proliferation, proteasome inhibition, and apoptosis induction. Inhibition of the proteasome was determined by levels of the proteasomal chymotrypsin-like activity, by ubiquitinated proteins, and by accumulation of proteasome target proteins in extracts of the treated cells or tumors. Apoptotic cell death was measured by capase-3/caspase-7 activation, poly(ADP-ribose) polymerase cleavage, and immunohistochemistry for terminal nucleotidyl transferase-mediated nick end labeling positivity.
Results We report for the first time that apigenin inhibits the proteasomal chymotrypsin-like activity and induces apoptosis not only in cultured MDA-MB-231 cells but also in MDA-MB-231 xenografts. Furthermore, while apigenin has antibreast tumor activity, no apparent toxicity to the tested animals was observed.
Conclusion We have shown that apigenin is an effective proteasome inhibitor in cultured breast cancer cells and in breast cancer xenografts. Furthermore, apigenin induces apoptotic cell death in human breast cancer cells and exhibits anticancer activities in tumors. The results suggest its potential benefits in breast cancer prevention and treatment.
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.