Sima Ni, Sun Wei, Gorshkov Kirill, Shen Min, Huang Wei, Zhu Wenge, Xie Xing, Zheng Wei, Cheng Xiaodong
Department of Gynecologic Oncology, Women's Reproductive Health Laboratory of Zhejiang Province, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China; National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Transl Oncol. 2018 Aug;11(4):1053-1064. doi: 10.1016/j.tranon.2018.06.002. Epub 2018 Jul 5.
Drug resistance to chemotherapy occurs in many ovarian cancer patients resulting in failure of treatment. Exploration of drug resistance mechanisms and identification of new therapeutics that overcome the drug resistance can improve patient prognosis. Following a quantitative combination screen of 6060 approved drugs and bioactive compounds in a cisplatin-resistant A2780-cis ovarian cancer cell line, 38 active compounds with ICs under 1 μM suppressed the growth of cisplatin-resistant ovarian cancer cells. Among these confirmed compounds, CUDC-101, OSU-03012, oligomycin A, VE-821, or Torin2 in a combination with cisplatin restored cisplatin's apoptotic response in the A2780-cis cells, while SR-3306, GSK-923295, SNX-5422, AT-13387, and PF-05212384 directly suppressed the growth of A2780-cis cells. One of the mechanisms for overcoming cisplatin resistance in these cells is mediated by the inhibition of epidermal growth factor receptor (EGFR), though not all the EGFR inhibitors are equally active. The increased levels of total EGFR and phosphorylated-EGFR (p-EGFR) in the A2780-cis cells were reduced after the combined treatment of cisplatin with EGFR inhibitors. In addition, a knockdown of EGFR mRNA reduced cisplatin resistance in the A2780-cis cells. Therefore, the top active compounds identified in this work can be studied further as potential treatments for cisplatin-resistant ovarian cancer. The quantitative combinational screening approach is a useful method for identifying effective compounds and drug combinations against drug-resistant cancer cells.
许多卵巢癌患者会出现对化疗的耐药性，导致治疗失败。探索耐药机制并确定克服耐药性的新疗法可以改善患者预后。在对顺铂耐药的A2780-cis卵巢癌细胞系中对6060种已批准药物和生物活性化合物进行定量联合筛选后，38种IC50低于1 μM的活性化合物抑制了顺铂耐药卵巢癌细胞的生长。在这些已确认的化合物中，CUDC-101、OSU-03012、寡霉素A、VE-821或Torin2与顺铂联合使用可恢复顺铂在A2780-cis细胞中的凋亡反应，而SR-3306、GSK-923295、SNX-5422、AT-13387和PF-05212384可直接抑制A2780-cis细胞的生长。这些细胞中克服顺铂耐药性的机制之一是通过抑制表皮生长因子受体（EGFR）介导的，尽管并非所有的EGFR抑制剂都具有同等活性。顺铂与EGFR抑制剂联合治疗后，A2780-cis细胞中总EGFR和磷酸化EGFR（p-EGFR）水平升高的情况有所降低。此外，敲低EGFR mRNA可降低A2780-cis细胞中的顺铂耐药性。因此，本研究中确定的顶级活性化合物可作为顺铂耐药卵巢癌的潜在治疗方法进行进一步研究。定量联合筛选方法是一种识别针对耐药癌细胞的有效化合物和药物组合的有用方法。
