1. Academic Validation
  2. The bromodomain and extra-terminal domain inhibitor JQ1 synergistically sensitizes human colorectal cancer cells to topoisomerase I inhibitors through repression of Mre11-mediated DNA repair pathway

The bromodomain and extra-terminal domain inhibitor JQ1 synergistically sensitizes human colorectal cancer cells to topoisomerase I inhibitors through repression of Mre11-mediated DNA repair pathway

  • Invest New Drugs. 2021 Apr;39(2):362-376. doi: 10.1007/s10637-020-01014-0.
Linping Lei 1 2 Xuqin Xie 1 2 Long He 1 2 Keling Chen 1 2 Zhaoying Lv 1 2 Bin Zhou 1 2 Yuan Li 1 2 Wenjun Hu 1 2 Zongguang Zhou 3 4
Affiliations

Affiliations

  • 1 Laboratory of Digestive Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2 Department of Gastrointestinal Surgery, West China Hospital, West China School of Medicine, Sichuan University, No. 37 Guoxue Lane, Chengdu, 610041, China.
  • 3 Laboratory of Digestive Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China. zhou767@163.com.
  • 4 Department of Gastrointestinal Surgery, West China Hospital, West China School of Medicine, Sichuan University, No. 37 Guoxue Lane, Chengdu, 610041, China. zhou767@163.com.
Abstract

Camptothecin (CPT) and its derivatives, irinotecan and topotecan are specific Topoisomerase I (Top1) inhibitors and potent Anticancer drugs. Mechanistically, they induce DNA double-strand breaks (DSBs). Although CPT is an effective chemotherapeutic agent used in the management of advanced colorectal Cancer, there exist associated side effects. Herein, we aimed to establish novel drug combinations that can effectively aid in managing the CPT-related side effects. Besides, bromodomain and extra-terminal domain (BET) inhibitors have proved as promising drugs that target epigenetic mechanisms in various cancers, they alter DNA repair processes, hence are a potential candidate for CPT synthetic lethality. A novel BET inhibitor JQ1 synergized with CPT, exerted antiproliferative effects. Through cell cycle analyses and Apoptosis assays, we revealed that a combination of CPT and JQ1 induces subG1-phase arrest and enhances cell Apoptosis. This combination increased the intensity of γ-H2AX staining, a specific marker of DSBs. Moreover, colorectal Cancer cells highly expressing Top1 showed greater sensitivity to JQ1, which was lowered through the lentiviral shRNA-mediated knockdown of Top1. JQ1, combined with CPT, impeded the recruitment of the Mre11-mediated MRN complex. Finally, JQ1 enhanced the in vivo sensitivity of tumors to CPT without inducing toxicity. These results demonstrate that a combination of BET inhibitor with Top1 inhibitor is safe and exerts positive chemotherapeutic effects in colorectal Cancer.

Keywords

BET inhibitor; Colorectal cancer; Combination therapy; DNA repair; Topoisomerase I inhibitor.

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