Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain; Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain.
Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain; Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain; Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain.
Neoplasia. 2021 May;23(5):515-528. doi: 10.1016/j.neo.2021.04.003. Epub 2021 Apr 27.
Ovarian cancer (OC) is the deadliest gynecologic malignancy, which is mainly due to late-stage diagnosis and chemotherapy resistance. Therefore, new and more effective treatments are urgently needed. The in vitro effects of Panobinostat (LBH), a histone deacetylase inhibitor that exerts pleiotropic antitumor effects but induces autophagy, in combination with Chloroquine (CQ), an autophagy inhibitor that avoid this cell survival mechanism, were evaluated in 4 OC cell lines. LBH and CQ inhibited ovarian cancer cell proliferation and induced apoptosis, and a strong synergistic effect was observed when combined. Deeping into their mechanisms of action we show that, in addition to autophagy modulation, treatment with CQ increased reactive oxygen species (ROS) causing DNA double strand breaks (DSBs), whereas LBH inhibited their repair by avoiding the correct recruitment of the recombinase Rad51 to DSBs. Interestingly, CQ-induced DSBs and cell death caused by CQ/LBH combination were largely abolished by the ROS scavenger N-Acetylcysteine, revealing the critical role of DSB generation in CQ/LBH-induced lethality. This role was also manifested by the synergy found when we combined CQ with Mirin, a well-known homologous recombination repair inhibitor. Altogether, our results provide a rationale for the clinical investigation of CQ/LBH combination in ovarian cancer.
卵巢癌（OC）是致命的妇科恶性肿瘤，主要是由于晚期诊断和化疗耐药。因此，迫切需要新的、更有效的治疗方法。本文评估了组蛋白去乙酰化酶抑制剂 Panobinostat（LBH）联合自噬抑制剂氯喹（CQ）在 4 种 OC 细胞系中的体外作用。LBH 和 CQ 抑制卵巢癌细胞增殖并诱导细胞凋亡，联合使用时观察到强烈的协同作用。深入研究其作用机制，我们发现，除了自噬调节外，CQ 处理还会增加活性氧（ROS），导致 DNA 双链断裂（DSB），而 LBH 通过避免重组酶 Rad51 正确募集到 DSB 上来抑制其修复。有趣的是，ROS 清除剂 N-乙酰半胱氨酸大大消除了 CQ/LBH 组合诱导的 DSB 和细胞死亡，这揭示了 DSB 的产生在 CQ/LBH 诱导的致死性中起关键作用。当我们将 CQ 与 Mirin（一种众所周知的同源重组修复抑制剂）联合使用时，也发现了这种协同作用。总之，我们的研究结果为 CQ/LBH 联合在卵巢癌中的临床研究提供了依据。
