Resveratrol increases the sensitivity of breast cancer MDA-MB-231 cell line to cisplatin by regulating intrinsic apoptosis

Document Type : Original Article


Department of Biochemistry, Faculty of Pharmacy, Anadolu University, Eskişehir, Turkey


Objective(s): Breast cancer is one of the most common types of cancer. Chemotherapeutic agents used during treatment induce cytotoxic effects also on normal cells in the tissues. Anti-oxidants used in combination with chemotherapeutic agents have been shown to reduce toxicity on normal cells to a minimum, and some anti-oxidant substances have chemotherapeutic effects. Cisplatin (CDDP) is a platinum class drug that is used clinically in the treatment of many cancers. Resveratrol (RSV) is a natural polyphenol with potent anti-oxidant and anticancer properties. In this study, we aimed to investigate apoptotic effects of using cisplatin and RSV alone or in combined treatment of MDA-MB-231 cells.
Materials and Methods: The cytotoxic effects of the drugs on MDA-MB-231 cells were determined by MTT method. Subsequently, the change in CDDP-induced apoptotic effect after RSV addition was examined using the AnnexinV FITC labeling, and TUNEL staining method. Activation of caspase-9, -3 in MDA-MB-231 cells was measured by flow cytometer. The mitochondrial membrane potential (MMP), the major factor on the intrinsic pathway, was measured using flowcytometry.
Results: The combined dose (23 μM CDDP + 72 μM RSV) produced more cytotoxicity than the agents used alone, leading to early apoptosis (8.2%), 31% depolarization, and 23% DNA fragmentation. Caspase-9 was found to be 30.5% in this combined group and caspase-3 was 26.3%.
Conclusion: RSV, an effective anti-oxidant, and CDDP as an effective drug in cancer treatment, were found to increase apoptosis when given in the MDA-MB-231 cell.


1. Sun Y, Zhou QM, Lu YY, Zhang H, Chen QL, Zhao M, et al. Resveratrol ınhibits the migration and metastasis of mda-mb-231 human breast cancer by reversing TGF-β1-ınduced epithelial-mesenchymal transition.  Molecules 2019;24:1131-1146.
    2.    Dewangan J, Tandon D, Srivastava S, Verma AK, Yapuri A, Rath SK. Novel combination of salinomycin and resveratrol synergistically enhances the antiproliferative and pro-apoptotic effects on human breast cancer cells.  Apoptosis 2017;22:1246–1259.
    3.    Yang C,  Guo Y,  Huang TS ,  Zhao J ,  Huang XJ ,  Tang HX,  et al. Asiatic acid protects against cisplatin-ınduced acute kidney ınjury via anti-apoptosis and anti-ınflammation. Biomed Pharmacother 2018;107:1354-1362.
    4.    Bhadri N, Sanji T, Guggilla HM, Razdan R. Amelioration of behavioural, biochemical, and
neurophysiological deficits by combination of monosodium glutamate with resveratrol/alpha-lipoic
acid/coenzyme Q10 in rat model of cisplatin-ınduced peripheral neuropathy. ScientificWorldJournal 2013; 2013:565813-565820.
    5.    Ko JH, Sethi G , Um JY , Shanmugam MK , Arfuso F , Kumar AP,  et al. The role of resveratrol in cancer therapy. Int J Mol Sci 2017;18:2589-2624.
    6.    Shakibaei M, Harikumar KB, Aggarwal BB. Review: Resveratrol addiction: To die or not to die. Mol Nutr Food Res 2009;53:115-128.
    7.    Carter LG, D’Orazio JA, Pearson KJ. Resveratrol and cancer: Focus on in vivo evidence.  Endocr Relat Cancer 2014;21:209-225.
    8.    Akinwumi BC, Bordun M, Anderson HD. Biological activities of stilbenoids. Int J Mol Sci 2018;19:792-816.
    9.    Gupta CS, Kannappan R, Reuter S,  Kim JH, Aggarwal BB. Chemosensitization of tumors by resveratrol. Ann N Y Acad Sci 2011;1215:150-160.
    10.    Hong Bin W, Da LH, Xue Y, Jing BW. Pterostilbene (3’,5’-dimethoxy-resveratrol) exerts potent antitumor effects in HeLa human cervical cancer cells via disruption of mitochondrial membrane potential, apoptosis induction and targeting m-TOR/PI3K/Akt signalling pathway. J BUON 2018;23:1384-1389.
    11.    Tor YS, Yazan LS, Foo JB, Wibowo A, Ismail N, Cheah YK, et al. Induction of apoptosis in MCF-7 cells via oxidative stress generation, mitochondria dependentand caspase-ındependent pathway by ethyl acetate extract of dillenia suffruticosa and ıts chemical profile. PLoS One 2015;5:10:e0127441.
    12.    Wang X, Feng Y, Wang N, Cheung F, Tan HY, Zhong S, et al. Chinese medicines ınduce cell death: the molecular and cellular mechanisms for cancer therapy. Biomed Res Int 2014;2014:1-14.
    13.    Xue YQ, Di JM, Luo Y, Cheng KJ, Wei X, Shi Z. Resveratrol oligomers for the prevention and treatment of cancers. Oxid Med Cell Longev 2014;2014:1-9.
    14.     Singh N, Nigam M,  Ranjan V,  Zaidi D, Garg VK,  Sharma S,  et al. Resveratrol as an adjunct therapy in cyclophosphamide-treated MCF- 7 cells and breast tumor explants. Cancer Sci 2011;102:1059-1067.
    15.    Kisková T,  Jendželovský R,  Rentsen E, Maier-Salamon A,  Kokošová N,  Papčová  Z, et al.  Resveratrol enhances the chemopreventive effect of celecoxib in chemically induced breast cancer in rats. Eur J Cancer Prev 2014;23:6:506-513.
    16.    Mikuła-Pietrasik J,  Sosińska P,  Murias M,  Wierzchowski M,  Brewińska-Olchowik M,  Piwocka K,  et al.  High potency of a novel resveratrol derivative, 3,3,4,4-tetrahydroxy-trans-stilbene, against ovarian cancer is associated with an oxidative stress-mediated imbalance between DNA damage accumulation and repair. Oxid Med Cell Longev 2015;2015:135691-135705.
    17.    Jiang CP, Ding H, Shi DH, Wang YR, Li EG, Wu JH. Pro-apoptotic effects of tectorigenin on human hepatocellular carcinoma HepG2 cells. World J Gastroenterol 2012;21:18:1753-1764.
    18.    Soto-Cerrato V, Montaner B, Martinell M, Vilaseca M, Giralt E, Pérez-Tomás R. Cell cycle arrest and proapoptotic effects of the anticancer cyclodepsipeptide serratamolide (AT514) are independent of p53 status in breast cancer cells. Biochem Pharmacol 2005;19:71:32-41.
    19.    Li W, Shi Y, Wang R, Pan L, Ma L, Jin F. Resveratrol promotes the sensitivity of small-cell lung cancer H446 cells to cisplatin by regulating intrinsic apoptosis. Int J Oncol 2018;53:2123-2130.
    20.    Özdemir F, Apaydın E, Önder Nİ, Şen M, Ayrım A, Öğünç Y, et al. Apoptotic effects of ε-viniferin in combination with cis-platin in C6 cells. Cytotechnology 2018;70:1061-1073.
    21.    Lijie MA, Li W, Wang R, Nan Y, Wang Q, Liu W, et al. Resveratrol enhanced anticancer effects of cisplatin on non-small cell lung cancer cell lines by inducing mitochondrial dysfunction and cell apoptosis. Int J Oncol 2015;47:1460-1468.
    22.    Yamaguchi Y, Miura M. Programmed cell death and caspase functions during neural development. Curr Top Dev Biol 2015;114:159–184.
    23.    Mukherjee A, Williams DW. More alive than dead: nonapoptotic roles for caspases in neuronal development, plasticity and disease. Cell Death Differ 2017;24:1411–1421.
    24.    Billard C, Izard JC, Roman V, Kern C, Mathiot C, Mentz F, et al. Comparative antiproliferative and apoptotic effects of resveratrol, epsilon-viniferin and vine-shots derived polyphenols (vineatrols) on chronic B lymphocytic leukemia cells and normal human lymphocytes. Leuk Lymphoma 2002;43:1991–2002.
    25.    Ferry-Dumazet H, Garnier O, Mamani-Matsuda M, Vercauteren J, Belloc F,  Billiard C, et al. Resveratrol inhibits the growth and induces the apoptosis of both normal and leukemic hematopoietic cells. Carcinogenesis 2002;23:1327–1333.
    26.    Jakubowicz-Gil J, Langner E, Badziul D, Wertel I, Rzeski W. Apoptosis induction in human glioblastoma multiforme T98G cells upon temozolomide and quercetin treatment. Tumour Biol 2013;34:2367– 2378.
    27.    Bobermin LD, Souza DO, Gonçalves CA, Santos AQ. Resveratrol prevents ammonia-induced mitochondrial dysfunction and cellular redox imbalance in C6 astroglial cells. Nutr Neurosci 2018;21:276-285.
    28.    Ozdemir F, İncesu Z, Şen M, Onder Nİ, Dikmen M. Implications of enhanced effectiveness of vincristine sulfate/ε-viniferin combination compared to vincristine sulfate only on HepG2 cells. Dicle Med J 2016; 43:534–541.