同时抑制BET和MAPK以有效治疗卵巢癌。
Concomitant BET and MAPK blockade for effective treatment of ovarian cancer.
作者信息
Jing Ying, Zhang Zhenfeng, Ma Pengfei, An Shimin, Shen Ying, Zhu Liang, Zhuang Guanglei
机构信息
State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, RenJi Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
出版信息
Oncotarget. 2016 Jan 19;7(3):2545-54. doi: 10.18632/oncotarget.6309.
Ovarian cancer is the most lethal gynecologic malignancy, and it is imperative to develop new treatments to ameliorate patient survival. Using an anti-cancer drug library containing 180 small molecule inhibitors, we performed a high-content image-based screen and found that BET and MEK inhibitors are among the candidates which were able to effectively inhibit ovarian cancer cell growth. However, BET inhibition alone was largely cytostatic, possibly due to feedback activation of the MAPK pathway. Consequently, the combination of MEK and BET inhibitors suppressed both cell proliferation and survival, and was more efficacious than single agent. Mechanistically, BET and MEK inhibitors exerted synergistic effects on apoptosis regulators including BIM and BAD. Our findings support concomitant BET and MAPK blockade as an effective therapeutic strategy in ovarian cancer.
卵巢癌是最致命的妇科恶性肿瘤，开发新的治疗方法以改善患者生存率势在必行。我们使用一个包含180种小分子抑制剂的抗癌药物库进行了基于图像的高内涵筛选，发现BET和MEK抑制剂是能够有效抑制卵巢癌细胞生长的候选药物。然而，单独抑制BET在很大程度上具有细胞生长抑制作用，这可能是由于MAPK途径的反馈激活所致。因此，MEK和BET抑制剂联合使用可同时抑制细胞增殖和存活，且比单一药物更有效。从机制上讲，BET和MEK抑制剂对包括BIM和BAD在内的凋亡调节因子发挥协同作用。我们的研究结果支持同时阻断BET和MAPK作为卵巢癌的一种有效治疗策略。
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