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http://dx.doi.org/10.4162/nrp.2021.15.1.12

Synergistic anticancer activity of resveratrol in combination with docetaxel in prostate carcinoma cells  

Lee, Sang-Han (Department of Biochemistry, College of Medicine, Soonchunhyang University)
Lee, Yoon-Jin (Department of Biochemistry, College of Medicine, Soonchunhyang University)
Publication Information
Nutrition Research and Practice / v.15, no.1, 2021 , pp. 12-25 More about this Journal
Abstract
BACKGROUND/OBJECTIVES: The study was conducted to investigate the efficacy of the combination treatment of phytochemical resveratrol and the anticancer drug docetaxel (DTX) on prostate carcinoma LNCaP cells, including factors related to detailed cell death mechanisms. MATERIALS/METHODS: Using 2-dimensional monolayer and 3-dimensional spheroid culture systems, we examined the effects of resveratrol and DTX on cell viability, reactive oxygen species (ROS) levels, mitochondrial membrane potential, apoptosis, and necroptosis by MTT, flow cytometry, and Western blotting. RESULTS: At concentrations not toxic to normal human prostate epithelial cells, resveratrol effectively decreased the viability of LNCaP cells depending on concentration and time. The combination treatment of resveratrol and DTX exhibited synergistic inhibitory effects on cell growth, demonstrated by an increase in the sub-G0/G1 peak, Annexin V-phycoerythrin positive cell fraction, ROS, mitochondrial dysfunction, and DNA damage response as well as concurrent activation of apoptosis and necroptosis. Apoptosis and necroptosis were rescued by pretreatment with ROS scavenger N-acetylcysteine. CONCLUSIONS: We report resveratrol as an adjuvant drug candidate for improving the outcome of treatment in DTX therapy. Although the underlying mechanisms of necroptosis should be investigated comprehensively, targeting apoptosis and necroptosis simultaneously in the treatment of cancer can be a useful strategy for the development of promising drug candidates.
Keywords
Prostate cancer; resveratrol; docetaxel; apoptosis; necroptosis; oxidative stress;
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1 Zhang XQ, Huang XF, Hu XB, Zhan YH, An QX, Yang SM, Xia AJ, Yi J, Chen R, Mu SJ, Wu DC. Apogossypolone, a novel inhibitor of antiapoptotic Bcl-2 family proteins, induces autophagy of PC-3 and LNCaP prostate cancer cells in vitro. Asian J Androl 2010;12:697-708.   DOI
2 Wang X, Jiang W, Yan Y, Gong T, Han J, Tian Z, Zhou R. RNA viruses promote activation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathway. Nat Immunol 2014;15:1126-33.   DOI
3 Wang H, Sun L, Su L, Rizo J, Liu L, Wang LF, Wang FS, Wang X. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol Cell 2014;54:133-46.   DOI
4 Chen W, Zhou Z, Li L, Zhong CQ, Zheng X, Wu X, Zhang Y, Ma H, Huang D, Li W, Xia Z, Han J. Diverse sequence determinants control human and mouse receptor interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) interaction in necroptotic signaling. J Biol Chem 2013;288:16247-61.   DOI
5 Cheung-Ong K, Giaever G, Nislow C. DNA-damaging agents in cancer chemotherapy: serendipity and chemical biology. Chem Biol 2013;20:648-59.   DOI
6 Schmitt E, Paquet C, Beauchemin M, Bertrand R. DNA-damage response network at the crossroads of cell-cycle checkpoints, cellular senescence and apoptosis. J Zhejiang Univ Sci B 2007;8:377-97.   DOI
7 Pearl LH, Schierz AC, Ward SE, Al-Lazikani B, Pearl FM. Therapeutic opportunities within the DNA damage response. Nat Rev Cancer 2015;15:166-80.   DOI
8 Schulze-Osthoff K, Bakker AC, Vanhaesebroeck B, Beyaert R, Jacob WA, Fiers W. Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation. J Biol Chem 1992;267:5317-23.   DOI
9 Holmström KM, Finkel T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol 2014;15:411-21.   DOI
10 Redza-Dutordoir M, Averill-Bates DA. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim Biophys Acta 2016;1863:2977-92.   DOI
11 Qian Q, Chen W, Cao Y, Cao Q, Cui Y, Li Y, Wu J. Targeting reactive oxygen species in cancer via Chinese herbal medicine. Oxid Med Cell Longev 2019;2019:9240426.
12 Zanoni M, Piccinini F, Arienti C, Zamagni A, Santi S, Polico R, Bevilacqua A, Tesei A. 3D tumor spheroid models for in vitro therapeutic screening: a systematic approach to enhance the biological relevance of data obtained. Sci Rep 2016;6:19103.   DOI
13 Borges HL, Linden R, Wang JY. DNA damage-induced cell death: lessons from the central nervous system. Cell Res 2008;18:17-26.   DOI
14 Kai L, Levenson AS. Combination of resveratrol and antiandrogen flutamide has synergistic effect on androgen receptor inhibition in prostate cancer cells. Anticancer Res 2011;31:3323-30.
15 War AR, Paulraj MG, Ahmad T, Buhroo AA, Hussain B, Ignacimuthu S, Sharma HC. Mechanisms of plant defense against insect herbivores. Plant Signal Behav 2012;7:1306-20.   DOI
16 Salehi B, Mishra AP, Nigam M, Sener B, Kilic M, Sharifi-Rad M, Fokou PV, Martins N, Sharifi-Rad J. Resveratrol: a double-edged sword in health benefits. Biomedicines 2018;6:91.   DOI
17 Ko JH, Sethi G, Um JY, Shanmugam MK, Arfuso F, Kumar AP, Bishayee A, Ahn KS. The role of resveratrol in cancer therapy. Int J Mol Sci 2017;18:2589.   DOI
18 Takashina M, Inoue S, Tomihara K, Tomita K, Hattori K, Zhao QL, Suzuki T, Noguchi M, Ohashi W, Hattori Y. Different effect of resveratrol to induction of apoptosis depending on the type of human cancer cells. Int J Oncol 2017;50:787-97.   DOI
19 Hu S, Li X, Xu R, Ye L, Kong H, Zeng X, Wang H, Xie W. The synergistic effect of resveratrol in combination with cisplatin on apoptosis via modulating autophagy in A549 cells. Acta Biochim Biophys Sin (Shanghai) 2016;48:528-35.   DOI
20 Chang TW, Lin CY, Tzeng YJ, Lur HS. Synergistic combinations of tanshinone IIA and trans-resveratrol toward cisplatin-comparable cytotoxicity in HepG2 human hepatocellular carcinoma cells. Anticancer Res 2014;34:5473-80.
21 Singh SK, Banerjee S, Acosta EP, Lillard JW, Singh R. Resveratrol induces cell cycle arrest and apoptosis with docetaxel in prostate cancer cells via a p53/p21WAF1/CIP1 and p27KIP1 pathway. Oncotarget 2017;8:17216-28.   DOI
22 Sharma A, Boise LH, Shanmugam M. Cancer metabolism and the evasion of apoptotic cell death. Cancers (Basel) 2019;11:1144.   DOI
23 Zong WX, Thompson CB. Necrotic death as a cell fate. Genes Dev 2006;20:1-15.   DOI
24 Su Z, Yang Z, Xie L, DeWitt JP, Chen Y. Cancer therapy in the necroptosis era. Cell Death Differ 2016;23:748-56.   DOI
25 Gong Y, Fan Z, Luo G, Yang C, Huang Q, Fan K, Cheng H, Jin K, Ni Q, Yu X, Liu C. The role of necroptosis in cancer biology and therapy. Mol Cancer 2019;18:100.   DOI
26 Petrylak DP. Docetaxel for the treatment of hormone-refractory prostate cancer. Rev Urol 2003;5 Suppl 2:S14-21.
27 Adachi I, Watanabe T, Takashima S, Narabayashi M, Horikoshi N, Aoyama H, Taguchi T. A late phase II study of RP56976 (docetaxel) in patients with advanced or recurrent breast cancer. Br J Cancer 1996;73:210-6.   DOI
28 Hernandez-Vargas H, Palacios J, Moreno-Bueno G. Telling cells how to die: docetaxel therapy in cancer cell lines. Cell Cycle 2007;6:780-3.   DOI
29 Bayat Mokhtari R, Homayouni TS, Baluch N, Morgatskaya E, Kumar S, Das B, Yeger H. Combination therapy in combating cancer. Oncotarget 2017;8:38022-43.   DOI
30 Tsakalozou E, Eckman AM, Bae Y. Combination effects of docetaxel and doxorubicin in hormonerefractory prostate cancer cells. Biochem Res Int 2012;2012:832059.   DOI
31 Savarese DM, Halabi S, Hars V, Akerley WL, Taplin ME, Godley PA, Hussain A, Small EJ, Vogelzang NJ. Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB 9780. J Clin Oncol 2001;19:2509-16.   DOI
32 Budman DR, Calabro A, Kreis W. Synergistic and antagonistic combinations of drugs in human prostate cancer cell lines in vitro. Anticancer Drugs 2002;13:1011-6.   DOI
33 Lee YJ, Lee YJ, Im JH, Won SY, Kim YB, Cho MK, Nam HS, Choi YJ, Lee SH. Synergistic anti-cancer effects of resveratrol and chemotherapeutic agent clofarabine against human malignant mesothelioma MSTO-211H cells. Food Chem Toxicol 2013;52:61-8.   DOI
34 Chambers KF, Mosaad EM, Russell PJ, Clements JA, Doran MR 3rd. 3D cultures of prostate cancer cells cultured in a novel high-throughput culture platform are more resistant to chemotherapeutics compared to cells cultured in monolayer. PLoS One 2014;9:e111029.   DOI
35 Bray K, Chen HY, Karp CM, May M, Ganesan S, Karantza-Wadsworth V, DiPaola RS, White E. Bcl-2 modulation to activate apoptosis in prostate cancer. Mol Cancer Res 2009;7:1487-96.   DOI
36 Eguchi Y, Shimizu S, Tsujimoto Y. Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res 1997;57:1835-40.