Zhou Hai-Hong, Chen Xu, Cai Lu-Ya, Nan Xing-Wei, Chen Jia-Hua, Chen Xiu-Xiu, Yang Yang, Xing Zi-Hao, Wei Meng-Ning, Li Yao, Wang Sheng-Te, Liu Kun, Shi Zhi, Yan Xiao-Jian
Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Guangdong Provincial Key Laboratory of Bioengineering Medicine, Department of Cell Biology & Institute of Biomedicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou, China.
Front Oncol. 2019 Dec 19;9:1398. doi: 10.3389/fonc.2019.01398. eCollection 2019.
Overexpression of drug efflux transport ABCB1 is correlated with multidrug resistance (MDR) among cancer cells. Upregulation of ABCB1 accounts for the recurrence of resistance to docetaxel therapy in ovarian cancer with poor survival. Erastin is a novel and specific small molecule that targets SLC7A11 to induce ferroptosis. In the present research, we explored the synergistic effect of erastin and docetaxel in ovarian cancer. We confirmed that the co-delivery of erastin with docetaxel significantly decreased cell viability, promoted cell apoptosis, and induced cell cycle arrest at G2/M in ovarian cancer cells with ABCB1 overexpression. Mechanistically, erastin dominantly elevated the intracellular ABCB1 substrate levels by restricting the drug-efflux activity of ABCB1 without alteration of the expression of ABCB1. Consequently, erastin can reverse ABCB1-mediated docetaxel resistance in ovarian cancer, revealing that the combination of erastin and docetaxel may potentially offer an effective administration for chemo-resistant patients suffering from ovarian cancers.
药物外排转运体ABCB1的过表达与癌细胞的多药耐药（MDR）相关。ABCB1的上调是卵巢癌多西他赛治疗耐药复发且生存率低的原因。艾拉司丁是一种新型的特异性小分子，可靶向溶质载体家族7成员11（SLC7A11）诱导铁死亡。在本研究中，我们探究了艾拉司丁与多西他赛在卵巢癌中的协同作用。我们证实，在ABCB1过表达的卵巢癌细胞中，艾拉司丁与多西他赛共同给药可显著降低细胞活力、促进细胞凋亡并诱导细胞周期阻滞于G2/M期。机制上，艾拉司丁通过限制ABCB1的药物外排活性，显著提高细胞内ABCB1底物水平，而不改变ABCB1的表达。因此，艾拉司丁可逆转ABCB1介导的卵巢癌多西他赛耐药，这表明艾拉司丁与多西他赛联合使用可能为化疗耐药的卵巢癌患者提供一种有效的治疗方案。
