Korashy Hesham M, Maayah Zaid H, Al Anazi Fawaz E, Alsaad Abdulaziz M, Alanazi Ibrahim O, Belali Osamah M, Al-Atawi Fahad O, Alshamsan Aws
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia.
Anticancer Res. 2017 Sep;37(9):4899-4909. doi: 10.21873/anticanres.11899.
The tyrosine kinase inhibitor sunitinib was recently approved for use against gastrointestinal stromal tumors and advanced renal cell carcinoma. Yet, the protective effect of sunitinib against breast cancer has been poorly investigated. In this study, we investigated the antiproliferative and apoptogenic effects of sunitinib and the possible mechanism involved against the MCF7 human breast cancer cell line. Treatment of MCF7 cells with sunitinib caused concentration-dependent cell growth suppression due to apoptosis. Apoptotic death induced by sunitinib in MCF7 cells was mediated by activation of caspase-3 and p53 mRNA and protein expression and an increase in the percentage of apoptotic cells (40%) as determined by flow cytometry. Apoptosis was associated with a significant inhibition of nuclear factor-kappa B mRNA and protein expression. Mechanistically, blocking of de novo RNA synthesis by actinomycin D significantly inhibited sunitinib-induced expression of p53 mRNA, but not that of caspase-3, indicating involvement of a transcriptional mechanism. This apoptosis-mediated inhibition of MCF7 cell growth was attributed to inhibition of cell cycle-related genes (cyclin D1 and cyclin E2) and arrest of MCF7 cells in the G/M phase in the cell cycle, allowing up-regulation of expression of DNA repair genes such as x-ray repair cross-complementing protein 1. In addition, sunitinib exhibited concentration-dependent induction of oxidative stress genes (heme oxygenase 1 and glutathione transferase A1) through the nuclear factor erythroid 2-related factor 2 pathway. These findings lead us to propose that sunitinib suppressed the proliferation of MCF7 cells via cell-cycle arrest and apoptotic- and oxidative stress-mediated pathways.
酪氨酸激酶抑制剂舒尼替尼最近被批准用于治疗胃肠道间质瘤和晚期肾细胞癌。然而，舒尼替尼对乳腺癌的保护作用尚未得到充分研究。在本研究中，我们研究了舒尼替尼对MCF7人乳腺癌细胞系的抗增殖和促凋亡作用及其可能的机制。用舒尼替尼处理MCF7细胞会因凋亡导致浓度依赖性的细胞生长抑制。舒尼替尼在MCF7细胞中诱导的凋亡性死亡是由半胱天冬酶-3的激活、p53 mRNA和蛋白表达以及流式细胞术测定的凋亡细胞百分比增加（40%）介导的。凋亡与核因子-κB mRNA和蛋白表达的显著抑制有关。从机制上讲，放线菌素D阻断从头RNA合成显著抑制了舒尼替尼诱导的p53 mRNA表达，但对半胱天冬酶-3的表达没有影响，表明涉及转录机制。这种凋亡介导的MCF7细胞生长抑制归因于对细胞周期相关基因（细胞周期蛋白D1和细胞周期蛋白E2）的抑制以及MCF7细胞在细胞周期的G/M期停滞，从而使DNA修复基因如X射线修复交叉互补蛋白1的表达上调。此外，舒尼替尼通过核因子红细胞2相关因子2途径表现出浓度依赖性地诱导氧化应激基因（血红素加氧酶1和谷胱甘肽转移酶A1）。这些发现使我们提出，舒尼替尼通过细胞周期停滞以及凋亡和氧化应激介导的途径抑制MCF7细胞的增殖。
