Protective Effects of Common Anthocyanidins against Genotoxic Damage Induced by Chemotherapeutic Drugs in Mice

Abstract

Experiments were performed to assess in mice the inhibitory effects of the anthocyanidins cyanidin, delphinidin, malvidin, and pelargonidin on genotoxic damage induced by the anticancer drugs cyclophosphamide, procarbazine, and cisplatin. Each anthocyanidin was administered 30 min before injecting the drug, and genotoxicity was assessed by measuring micronucleated polychromatic erythrocytes in bone marrow cells. In addition, we monitored the effect of anthocyanidins on apoptosis induced by cyclophosphamide and procarbazine. The results showed significant protective effects of cyanidin, delphinidin, malvidin, and pelargonidin against DNA damage induced by cyclophosphamide. With delphinidin and malvidin, a biphasic dose-response was observed for protection against cyclophosphamide. Dose-related reduction of genotoxicity was observed with pelargonidin against procarbazine. However with cyanidin, the medium dose of 2 mg/kg showed maximum protection against procarbazine. Cyanidin and pelargonidin significantly reduced the chromosomal damage induced by cisplatin. Furthermore, pre-treatment with these anthocyanidins reduced the level of apoptosis induced by cyclophosphamide and procarbazine. In conclusion, this study shows that anthocyanidins can reduce the efficacy of anticancer drugs for inducing DNA damage and apoptosis.

Key words

anthocyanidins - apoptosis - anticancer drugs - DNA damage - micronucleus test

• References

• 1 Cooke D, Steward WP, Gescher AJ, Marczylo T. Anthocyanins from fruits and vegetables – Does bright colour signal cancer chemopreventive activity?. Eur J Cancer 2005; 41: 1931-1940
• 2 He J, Guisti MM. Anthocyanins: natural colorants with health-promoting properties. Annu Rev Food Sci Technol 2010; 1: 163-187
• 3 Tsuda T. Dietary anthocyanin-rich plants: Biochemical basis and recent progress in health benefits studies. Mol Nutr Food Res 2012; 56: 159-170
• 4 Wang LS, Stoner GD. Anthocyanins and their role in cancer chemoprevention. Cancer Lett 2008; 269: 281-290
• 5 Zamora-Ros R, Knaze V, Luján-Barroso L, Slimani N, Romieu I, Touillaud M, Kaaks R, Teucher B, Mattiello A, Grioni S, Crowe F, Boeing H, Förster J, Quirós JR, Molina E, Huerta JM, Engeset D, Skeie G, Trichopoulou A, Dilis V, Tsiotas K, Peeters PH, Khaw KT, Wareham N, Bueno-de-Mesquita B, Ocké MC, Olsen A, Tjønneland A, Tumino R, Johansson G, Johansson I, Ardanaz E, Sacerdote C, Sonestedt E, Ericson U, Clavel-Chapelon F, Boutron-Ruault MC, Fagherazzi G, Salvini S, Amiano P, Riboli E, González CA. Estimation of the intake of anthocyanidins and their food sources in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Br J Nutr 2011; 106: 1090-1099
• 6 Abraham SK, Eckhardt A, Oli RG, Stopper H. Analysis of in vitro chemoprevention of genotoxic damage by phytochemicals, as single agents or as combinations. Mutat Res 2012; 744: 117-124
• 7 Abraham SK, Schupp N, Schmid U, Stopper H. Antigenotoxic effects of phytoestrogen pelargonidin chloride and the polyphenol chlorogenic acid. Mol Nutr Food Res 2007; 51: 880-887
• 8 Khandelwal N, Abraham SK. Intake of anthocyanidins pelargonidin and cyanidin reduces genotoxic stress in mice induced by diepoxybutane, urethane and endogenous nitrosation. Environ Toxicol Pharmacol 2014; 37: 837-843
• 9 DʼAndrea GM. Use of antioxidants during chemotherapy and radiotherapy should be avoided. CA Cancer J Clin 2005; 55: 319-321
• 10 Roos WP, Kaina B. DNA damage-induced cell death: From specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett 2013; 332: 237-248
• 11 Salganik RI. The benefits and hazards of antioxidants: controlling apoptosis and other protective mechanisms in cancer patients and the human population. J Am Coll Nutr 2001; 20: 464S-472S
• 12 Zeisel SH. Antioxidants suppress apoptosis. J Nutr 2004; 134: 3179S-3180S
• 13 Conklin KA. Dietary antioxidants during cancer chemotherapy: Impact on chemotherapeutic effectiveness and development of side effects. Nutr Cancer 2000; 37: 1-8
• 14 Takahashi H, Kosaka N, Nakagawa S. Alpha-tocopherol protects PC12 cells from hyperoxia-induced apoptosis. J Neurosci Res 1998; 52: 184-191
• 15 Salganik RI, Albright CD, Rodgers J, Kim J, Zeisel SH, Sivashinskiy MS, Van Dyke TA. Dietary antioxidant depletion: enhancement of tumor apoptosis and inhibition of brain tumor growth in transgenic mice. Carcinogenesis 2000; 21: 909-914
• 16 Somasundaram S, Edmund NA, Moore DT, Small GW, Shi YY, Orlowski RZ. Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. Cancer Res 2002; 62: 3868-3875
• 17 Prasad KN, Hernandez C, Edwards-Prasad J, Nelson J, Borus T, Robinson W. Modification of the effect of tamoxifen, cis-platin, DTIC, and interferon-α2b on human melanoma cells in culture by a mixture of vitamins. Nutr Cancer 1994; 22: 233-245
• 18 Teicher BA, Schwartz JL, Holden SA, Ara G, Northey D. In vivo modulation of several anticancer agents by β-carotene. Cancer Chemother Pharmacol 1994; 34: 235-241
• 19 Mendecki J, Friedenthal E, Dawson H, Seifter E. Beta-carotene reduces toxicity and carcinogenicity of cyclophosphamide in control and tumor-bearing mice (abstr). Adv Exp Med Biol 1994; 364: 177
• 20 Weisel T, Baum M, Eisenbrand G, Dietrich H, Will F, Stockis JP, Kulling S, Rüfer C, Johannes C, Janzowski C. An anthocyanin/polyphenol-rich fruit juice reduces oxidative DNA damage and increases glutathione level in healthy probands. Biotechnol J 2006; 1: 388-397
• 21 Duthie SJ. Berry phytochemicals, genomic stability and cancer: evidence for chemoprotection at several stages in the carcinogenic process. Mol Nutr Food Res 2007; 51: 665-674
• 22 Wu X, Beecher GR, Holden JM, Haytowitz DB, Gebhardt SE, Prior RL. Concentrations of anthocyanins in common foods in the United States and estimation of normal consumption. J Agric Food Chem 2006; 54: 4069-4075
• 23 McGhie TK, Walton MC. The bioavailability and absorption of anthocyanins: Towards a better understanding. Mol Nutr Food Res 2007; 51: 702-713
• 24 Gupta S, Saha B, Giri AK. Comparative antimutagenic and anticlastogenic effects of green tea and black tea: a review. Mutat Res 2002; 512: 37-65
• 25 Schmid W. The micronucleus test. Mutat Res 1975; 31: 9-15
• 26 Abraham SK, Khandelwal N. Ascorbic acid and dietary polyphenol combinations protect against genotoxic damage induced in mice by endogenous nitrosation. Mutat Res 2013; 757: 167-172