Generic placeholder image

Current Molecular Medicine


ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Research Article

Resveratrol Induces Apoptosis and Attenuates Proliferation of MCF-7 Cells in Combination with Radiation and Hyperthermia

Author(s): Peyman Amini, Saeedeh Jafari Nodooshan, Milad Ashrafizadeh, Seyed-Mohammad Eftekhari, Tayebeh Aryafar, Leila Khalafi, Ahmed Eleojo Musa, Seyed Rabie Mahdavi, Masoud Najafi* and Bagher Farhood*

Volume 21 , Issue 2 , 2021

Published on: 21 May, 2020

Page: [142 - 150] Pages: 9

DOI: 10.2174/1566524020666200521080953

Price: $65


Aim: In the current in vitro study, we tried to examine the possible role of resveratrol as a sensitizer in combination with radiotherapy or hyperthermia.

Background: Breast cancer is the most common malignancy for women and one of the most common worldwide. It has been suggested that using non-invasive radiotherapy alone cannot eliminate cancer cells. Hyperthermia, which is an adjuvant modality, induces cancer cell death mainly through apoptosis and necrosis. However, cancer cells can also develop resistance to this modality.

Objective: The objective of this study was to determine possible potentiation of apoptosis when MCF-7 cells treated with resveratrol before hyperthermia or radiotherapy.

Methods: MCF-7 cancer cells were treated with different doses of resveratrol to achieve IC50%. Afterwards, cells treated with the achieved concentration of resveratrol were exposed to radiation or hyperthermia. Proliferation, apoptosis and the expression of pro-apoptotic genes were evaluated using flow cytometry, MTT assay and real-time PCR. Results for each combination therapy were compared to radiotherapy or hyperthermia without resveratrol.

Results: Both irradiation or hyperthermia could reduce the viability of MCF-7 cells. Furthermore, the regulation of Bax and caspase genes increased, while Bcl-2 gene expression reduced. Resveratrol potentiated the effects of radiation and hyperthermia on MCF-7 cells.

Conclusion: Results of this study suggest that resveratrol is able to induce the regulation of pro-apoptotic genes and attenuate the viability of MCF-7 cells. This may indicate the sensitizing effect of resveratrol in combination with both radiotherapy and hyperthermia.

Keywords: Resveratrol, Radiation, Hyperthermia, MCF-7, Breast Cancer, Radiotherapy, Apoptosis, Bax, Bcl-2, Caspase 3, Viability.

DeSantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A. Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin 2017; 67(6): 439-48.
[] [PMID: 28972651]
Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017; 67(1): 7-30.
[] [PMID: 28055103]
Camarillo IG, Xiao F, Madhivanan S, et al. Electroporation-based therapies for cancer. Woodhead Publishing 2014; pp. 55-102.
Mondini M, Levy A, Meziani L, Milliat F, Deutsch E. Radiotherapy-immunotherapy combinations - perspectives and challenges. Mol Oncol 2020; 14(7): 1529-37.
[] [PMID: 32112478]
Jamalzadeh L, Ghafoori H, Aghamaali M, Sariri R. Induction of apoptosis in human breast cancer MCF-7 cells by a semi-synthetic derivative of artemisinin: a caspase-related mechanism. Iranian J Biotechnol 2017; 15(3): 157-65.
[] [PMID: 29845064]
Ahire V, Kumar A, Mishra KP, Kulkarni G. Ellagic acid enhances apoptotic sensitivity of breast cancer cells to γ-radiation. Nutr Cancer 2017; 69(6): 904-10.
[] [PMID: 28718725]
Willers H, Dahm-Daphi J, Powell SN. Repair of radiation damage to DNA. Br J Cancer 2004; 90(7): 1297-301.
[] [PMID: 15054444]
Luce A, Courtin A, Levalois C, et al. Death receptor pathways mediate targeted and non-targeted effects of ionizing radiations in breast cancer cells. Carcinogenesis 2009; 30(3): 432-9.
[] [PMID: 19126655]
Ware MJ, Krzykawska-Serda M, Chak-Shing Ho J, et al. Optimizing non-invasive radiofrequency hyperthermia treatment for improving drug delivery in 4T1 mouse breast cancer model. Sci Rep 2017; 7(1): 43961.
[] [PMID: 28287120]
Hamzehalipour Almaki J, Nasiri R, Idris A, Nasiri M, Abdul Majid FA, Losic D. Trastuzumab-decorated nanoparticles for in vitro and in vivo tumor-targeting hyperthermia of HER2+ breast cancer. J Mater Chem B Mater Biol Med 2017; 5(35): 7369-83.
[] [PMID: 32264187]
Notter M, Piazena H, Vaupel P. Hypofractionated re-irradiation of large-sized recurrent breast cancer with thermography-controlled, contact-free water-filtered infra-red-A hyperthermia: a retrospective study of 73 patients. Int J Hyperthermia 2017; 33(2): 227-36.
[] [PMID: 27618745]
Zhang Z-Q, Song S-C. Multiple hyperthermia-mediated release of TRAIL/SPION nanocomplex from thermosensitive polymeric hydrogels for combination cancer therapy. Biomaterials 2017; 132: 16-27.
[] [PMID: 28399459]
Zagar TM, Oleson JR, Vujaskovic Z, et al. Hyperthermia for locally advanced breast cancer. International journal of hyperthermia: the official journal of European Society for Hyperthermic Oncology. North American Hyperthermia Group 2010; 26(7): 618-24.
Rethfeldt E, Becker M, Koldovsky P. Whole-body hyperthermia in the treatment of breast cancer. Breast Cancer Research: BCR 2001; 3(Suppl. 1): A51-1.
Luzhna L, Lykkesfeldt AE, Kovalchuk O. Altered radiation responses of breast cancer cells resistant to hormonal therapy. Oncotarget 2015; 6(3): 1678-94.
[] [PMID: 25682200]
Hazra B, Ghosh S, Kumar A, Pandey BN. The prospective role of plant products in radiotherapy of cancer: a current overview. Front Pharmacol 2012; 2: 94.
[] [PMID: 22291649]
Sharma A, Kaur M, Katnoria JK, Nagpal AK. Polyphenols in food: cancer prevention and apoptosis induction. Curr Med Chem 2018; 25(36): 4740-57.
[] [PMID: 28990504]
Leon-Galicia I, Diaz-Chavez J, Albino-Sanchez ME, et al. Resveratrol decreases Rad51 expression and sensitizes cisplatin-resistant MCF-7 breast cancer cells. Oncol Rep 2018; 39(6): 3025-33.
[] [PMID: 29620223]
Joghatai M, Barari L, Mousavie Anijdan SH, Elmi MM. The evaluation of radio-sensitivity of mung bean proteins aqueous extract on MCF-7, hela and fibroblast cell line. Int J Radiat Biol 2018; 94(5): 478-87.
[] [PMID: 29482484]
Kuršvietienė L, Stanevičienė I, Mongirdienė A, Bernatonienė J. Multiplicity of effects and health benefits of resveratrol. Medicina (Kaunas) 2016; 52(3): 148-55.
[] [PMID: 27496184]
Chimento A, De Amicis F, Sirianni R, et al. Progress to improve oral bioavailability and beneficial effects of resveratrol. Int J Mol Sci 2019; 20(6): 1381.
[] [PMID: 30893846]
Ko JH, Sethi G, Um JY, et al. The Role of Resveratrol in Cancer Therapy. Int J Mol Sci 2017; 18(12)E2589
[] [PMID: 29194365]
Yousef M, Vlachogiannis IA, Tsiani E. Effects of resveratrol against lung cancer: In vitro and In vivo studies. Nutrients 2017; 9(11): 1231.
[] [PMID: 29125563]
Pozo-Guisado E, Merino JM, Mulero-Navarro S, et al. Resveratrol-induced apoptosis in MCF-7 human breast cancer cells involves a caspase-independent mechanism with downregulation of Bcl-2 and NF-kappaB. Int J Cancer 2005; 115(1): 74-84.
[] [PMID: 15688415]
Lee H, Park HJ, Park C-S, et al. Response of breast cancer cells and cancer stem cells to metformin and hyperthermia alone or combined. PLoS One 2014; 9(2)e87979
[] [PMID: 24505341]
Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 2001; 29(9)e45
[] [PMID: 11328886]
Keywan Mortezaee MN. Bagher Farhood, Amirhossein Ahmadi, Dheyauldeen Shabeeb, Ahmed Eleojo Musa, Resveratrol as an adjuvant for normal tissues protection and tumor sensitization. Curr Cancer Drug Targets 2019; •••: 19.
Morlé A, Garrido C, Micheau O. Hyperthermia restores apoptosis induced by death receptors through aggregation-induced c-FLIP cytosolic depletion. Cell Death Dis 2015; 6(2): e1633-3.
[] [PMID: 25675293]
Fu Q, Huang T, Wang X, et al. Association of elevated reactive oxygen species and hyperthermia induced radiosensitivity in cancer stem-like cells. Oncotarget 2017; 8(60): 101560-71.
[] [PMID: 29254186]
Roti Roti JL. Cellular responses to hyperthermia (40-46°C): cell killing and molecular events. Int J Hyperthermia 2008; 24(1): 3-15.
[] [PMID: 18214765]
Chang C-H, Lee C-Y, Lu C-C, et al. Resveratrol-induced autophagy and apoptosis in cisplatin-resistant human oral cancer CAR cells: A key role of AMPK and Akt/mTOR signaling. Int J Oncol 2017; 50(3): 873-82.
[] [PMID: 28197628]
Mortezaee K, Najafi M, Farhood B, Ahmadi A, Shabeeb D, Musa AE. Resveratrol as an adjuvant for normal tissues protection and tumor sensitization. Curr Cancer Drug Targets 2020; 20(2): 130-45.
[] [PMID: 31738153]
Heo JR, Kim SM, Hwang KA, Kang JH, Choi KC. Resveratrol induced reactive oxygen species and endoplasmic reticulum stress-mediated apoptosis, and cell cycle arrest in the A375SM malignant melanoma cell line. Int J Mol Med 2018; 42(3): 1427-35.
[] [PMID: 29916532]
Liu Q, Fang Q, Ji S, Han Z, Cheng W, Zhang H. Resveratrol-mediated apoptosis in renal cell carcinoma via the p53/AMP-activated protein kinase/mammalian target of rapamycin autophagy signaling pathway. Mol Med Rep 2018; 17(1): 502-8.
[PMID: 29115429]
Mukherjee S, Hussaini R, White R, et al. TriCurin, a synergistic formulation of curcumin, resveratrol, and epicatechin gallate, repolarizes tumor-associated macrophages and triggers an immune response to cause suppression of HPV+ tumors. Cancer Immunol Immunother 2018; 67(5): 761-74.
[] [PMID: 29453519]
Rauf A, Imran M, Butt MS, Nadeem M, Peters DG, Mubarak MS. Resveratrol as an anti-cancer agent: A review. Crit Rev Food Sci Nutr 2018; 58(9): 1428-47.
[] [PMID: 28001084]
Tino AB, Chitcholtan K, Sykes PH, Garrill A. Resveratrol and acetyl-resveratrol modulate activity of VEGF and IL-8 in ovarian cancer cell aggregates via attenuation of the NF-κB protein. J Ovarian Res 2016; 9(1): 84.
[] [PMID: 27906095]
Tilborghs S, Corthouts J, Verhoeven Y, et al. The role of Nuclear Factor-kappa B signaling in human cervical cancer. Crit Rev Oncol Hematol 2017; 120: 141-50.
[] [PMID: 29198328]
Colombo J, Jardim-Perassi BV, Ferreira JP, et al. Melatonin differentially modulates NF-KB expression in breast and liver cancer cells. Anticancer Agents Med Chem 2018; 18(12): 1688-94.
Xia L, Tan S, Zhou Y, et al. Role of the NFκB-signaling pathway in cancer. OncoTargets Ther 2018; 11: 2063-73.
[] [PMID: 29695914]
Xia Y, Shen S, Verma IM. NF-κB, an active player in human cancers. Cancer Immunol Res 2014; 2(9): 823-30.
[] [PMID: 25187272]
Farhood B, Khodamoradi E, Hoseini-Ghahfarokhi M, et al. TGF-β in radiotherapy: Mechanisms of tumor resistance and normal tissues injury. Pharmacol Res 2020; 155104745
[] [PMID: 32145401]
Shi Q, Chen Y-G. The functional switch of TGF-β signaling in breast cancer. Oncotarget 2019; 10(17): 1604-5.
[] [PMID: 30899430]
Mortezaee K, Najafi M, Farhood B, Ahmadi A, Shabeeb D, Musa AE. NF-κB targeting for overcoming tumor resistance and normal tissues toxicity. J Cell Physiol 2019; 234(10): 17187-204.
[] [PMID: 30912132]
Vriend LEM, van den Tempel N, Oei AL, et al. Boosting the effects of hyperthermia-based anticancer treatments by HSP90 inhibition. Oncotarget 2017; 8(57): 97490-503.
[] [PMID: 29228626]
Tu Y, Tian Y, Wu Y, Cui S. Clinical significance of heat shock proteins in gastric cancer following hyperthermia stress: Indications for hyperthermic intraperitoneal chemoperfusion therapy. Oncol Lett 2018; 15(6): 9385-91.
[] [PMID: 29946371]
Daunys S, Matulis D, Petrikaitė V. Synergistic activity of Hsp90 inhibitors and anticancer agents in pancreatic cancer cell cultures. Sci Rep 2019; 9(1): 16177.
[] [PMID: 31700053]
IJff M, van Oorschot B, Oei AL, et al. Enhancement of radiation effectiveness in cervical cancer cells by combining ionizing radiation with hyperthermia and molecular targeting agents. Int J Mol Sci 2018; 19(8): 2420.
[] [PMID: 30115874]
Cardile V, Scifo C, Russo A, et al. Involvement of HSP70 in resveratrol-induced apoptosis of human prostate cancer. Anticancer Res 2003; 23(6C): 4921-6.
[PMID: 14981946]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy