Atorvastatin Sensitizes Breast and Lung Cancer Cells to Ionizing Radiation

Document Type : Research article


1 Department of Radiopharmacy, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.

2 Department of Radiology and Radiation Oncology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

3 Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.

4 Immunogenetics Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.


Tumour cells may be resistant to radiotherapy that results in unsuccessful cancer treatment in patients. The aim of this study was to evaluate the sensitizing effect of atorvastatin (ATV) on breast cancer (MDA-MB-231) and non-small cell lung cancer (A-549) cells following exposure to ionizing radiation (IR). These cells were treated with ATV and exposed to X-ray at dose 4 Gy. The radiosensitizing effects of ATV were evaluated by flow cytometry and anti-proliferation assays. The production of reactive oxygen species (ROS) was determined in irradiated and treated cells with ATV. The findings of this study showed that ATV increased the percentage of apoptotic cells in irradiated breast and lung cancer cells. ATV exhibited anti-proliferative effect on cancer cells and increased cell death induced by IR. ATV increased ROS production in irradiated cells. The present study demonstrates that ATV has radiosensitizing effect on breast and lung cancer cells through increasing apoptosis, ROS production and cell death induced by IR.

Graphical Abstract

Atorvastatin Sensitizes Breast and Lung Cancer Cells to Ionizing Radiation


Main Subjects

(1)   Hosseinimehr SJ. Flavonoids and genomic instability induced by ionizing radiation. Drug discovery today. (2010) 15:907-918.
(2)   Hosseinimehr SJ. The use of angiotensin II receptor antagonists to increase the efficacy of radiotherapy in cancer treatment. Future Oncol. (2014) 10:2381-2390.
(3)   Salehifar E, Hosseinimehr SJ. The use of cyclooxygenase-2 inhibitors for improvement of efficacy of radiotherapy in cancers. Drug Discov Today. (2016) 21:654-662.
(4)   Linam J, Yang LX. Recent developments in radiosensitization. Anticancer Res. (2015) 35:2479-2485.
(5)   Hosseinimehr SJ, Ahmadi A, Beiki D, Habibi E, Mahmoudzadeh A. Protective effects of hesperidin against genotoxicity induced by (99m)Tc-MIBI in human cultured lymphocyte cells. Nucl Med Biol. (2009) 36:863-867.
(6)   Hosseinimehr SJ, Zakaryaee V, Froughizadeh M. Oral oxymetholone reduces mortality induced by gamma irradiation in mice through stimulation of hematopoietic cells. Mol Cell Biochem. (2006) 287:193-199.
(7)   Srivastava M, Raghavan SC. DNA double-strand break repair inhibitors as cancer therapeutics. Chem Biol. (2015) 22:17-29.
(8)   Bjarnadottir O, Kimbung S, Johansson I, Veerla S, Jonsson M, Bendahl PO, et al. Global Transcriptional Changes Following Statin Treatment in Breast Cancer. Clin Cancer Res. (2015) 21:3402-3411.
(9)   Kang M, Jeong CW, Ku JH, Kwak C, Kim HH. Inhibition of autophagy potentiates atorvastatin-induced apoptotic cell death in human bladder cancer cells in vitro. Int J Mol Sci. (2014) 15:8106-8121.
(10)   Wilke M, Gobel A, Rauner M, Benad-Mehner P, Schutze N, Fussel S, et al. Zoledronic acid and atorvastatin inhibit alphavbeta3-mediated adhesion of breast cancer cells. J Bone Oncol. (2014) 3:10-17.
(11)   Oliveira KA, Dal-Cim T, Lopes FG, Ludka FK, Nedel CB, Tasca CI. Atorvastatin Promotes Cytotoxicity and Reduces Migration and Proliferation of Human A172 Glioma Cells. Mol Neurobiol. (2018) 55:1509-1523.
(12)   Toepfer N, Childress C, Parikh A, Rukstalis D, Yang W. Atorvastatin induces autophagy in prostate cancer PC3 cells through activation of LC3 transcription. Cancer Biol Ther. (2011) 12:691-699.
(13)   Hosseinimehr SJ, Izakmehri M, Ghasemi A. In vitro protective effect of atorvastatin against ionizing radiation induced genotoxicity in human lymphocytes. Cell Mol Biol (Noisy-le-grand). (2015) 61:68-71.
(14)   Naeimi RA, Talebpour Amiri F, Khalatbary AR, Ghasemi A, Zargari M, Ghesemi M, et al. Atorvastatin mitigates testicular injuries induced by ionizing radiation in mice. Reprod Toxicol. (2017) 72:115-121.
(15)   Talebpour Amiri F, Hamzeh M, Naeimi RA, Ghasemi A, Hosseinimehr SJ. Radioprotective effect of atorvastatin against ionizing radiation-induced nephrotoxicity in mice. Int J Radiat Biol. (2018) 94:106-113.
(16)   Ghasemi A, Ghashghai Z, Akbari J, Yazdani-Charati J, Salehifar E, Hosseinimehr SJ. Topical atorvastatin 1% for prevention of skin toxicity in patients receiving radiation therapy for breast cancer: a randomized, double-blind, placebo-controlled trial. Eur J Clin Pharmacol. (2019) 75:171-178.
(17)   Yazdannejat H, Hosseinimehr SJ, Ghasemi A, Pourfallah TA, Rafiei A. Losartan sensitizes selectively prostate cancer cell to ionizing radiation. Cell Mol Biol (Noisy-le-grand). (2016) 62:30-33.
(18)   Fei Z, Gu W, Xie R, Su H, Jiang Y. Artesunate enhances radiosensitivity of esophageal cancer cells by inhibiting the repair of DNA damage. J Pharmacol Sci. (2018) 138:131-137.
(19)   Hosseinimehr SJ, Safavi Z, Kangarani Farahani S, Noaparst Z, Ghasemi A, Asgarian-Omran H. The synergistic effect of mefenamic acid with ionizing radiation in colon cancer. J Bioenerg Biomembr. (2019) 51:249-257.
(20)   Ji K, Sun X, Liu Y, Du L, Wang Y, He N, et al. Regulation of Apoptosis and Radiation Sensitization in Lung Cancer Cells via the Sirt1/NF-kappaB/Smac Pathway. Cell Physiol Biochem. (2018) 48:304-316.
(21)   He Z, Yuan J, Qi P, Zhang L, Wang Z. Atorvastatin induces autophagic cell death in prostate cancer cells in vitro. Mol Med Rep. (2015) 11:4403-4408.
(22)   Martinez TA, Zeybek ND, Muftuoglu S. Evaluation of the Cytotoxic and Autophagic Effects of Atorvastatin on Mcf-7 Breast Cancer Cells. Balkan Med J. (2018).
(23)   Li J, Liu J, Liang Z, He F, Yang L, Li P, et al. Simvastatin and Atorvastatin inhibit DNA replication licensing factor MCM7 and effectively suppress RB-deficient tumors growth. Cell Death Dis. (2017) 8:e2673.
(24)   Liu H, Liang SL, Kumar S, Weyman CM, Liu W, Zhou A. Statins induce apoptosis in ovarian cancer cells through activation of JNK and enhancement of Bim expression. Cancer Chemother Pharmacol. (2009) 63:997-1005.
(25)   Sanchez CA, Rodriguez E, Varela E, Zapata E, Paez A, Masso FA, et al. Statin-induced inhibition of MCF-7 breast cancer cell proliferation is related to cell cycle arrest and apoptotic and necrotic cell death mediated by an enhanced oxidative stress. Cancer Invest. (2008) 26:698-707.
(26)   Zhang P, He D, Song E, Jiang M, Song Y. Celecoxib enhances the sensitivity of non-small-cell lung cancer cells to radiation-induced apoptosis through downregulation of the Akt/mTOR signaling pathway and COX-2 expression. PLoS One. (2019) 14:e0223760.
(27)   Choo DW, Goh SH, Cho YW, Baek HJ, Park EJ, Motoyama N, et al. CHK2 is involved in the p53-independent radiosensitizing effects of valproic acid. Oncol Lett. (2017) 13:2591-2598.
(28)   Qi R, Jin W, Wang J, Yi Q, Yu M, Xu S, et al. Oleanolic acid enhances the radiosensitivity of tumor cells under mimetic hypoxia through the reduction in intracellular GSH content and HIF-1alpha expression. Oncol Rep. (2014) 31:2399-2406.
(29)   Kijima T, Koga F, Fujii Y, Yoshida S, Tatokoro M, Kihara K. Zoledronic acid sensitizes renal cell carcinoma cells to radiation by downregulating STAT1. PLoS One. (2013) 8:e64615.
(30)   Patel K, Doudican NA, Schiff PB, Orlow SJ. Albendazole sensitizes cancer cells to ionizing radiation. Radiat Oncol. (2011) 6:160.
(31)   Gewirtz DA, Hilliker ML, Wilson EN. Promotion of autophagy as a mechanism for radiation sensitization of breast tumor cells. Radiother Oncol. (2009) 92:323-328.
(32)   Jones HM, Fang Z, Sun W, Clark LH, Stine JE, Tran AQ, et al. Atorvastatin exhibits anti-tumorigenic and anti-metastatic effects in ovarian cancer in vitro. Am J Cancer Res. (2017) 7:2478-2490.