The bromodomain and extra-terminal domain inhibitor JQ1 synergistically sensitizes human colorectal cancer cells to topo
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PRECLINICAL STUDIES
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 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 1,2 Received: 13 August 2020 / Accepted: 21 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary 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 Colorectal cancer . Topoisomerase I inhibitor . BET inhibitor . DNA repair . Combination therapy
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10637-020-01014-0) contains supplementary material, which is available to authorized users. * Zongguang Zhou [email protected] Wenjun Hu [email protected] 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
Colorectal cancer (CRC) is among the highly prevalent cancers in men and women, and the second most cause of cancerrelated deaths across the globe [1]. Despite the curative advances of cancer therapy made in CRC, chemotherapy is still considered one of the primary management approach for CRC [2]. Conventionally, 5- fluorouracil (5-FU) and its analogs we
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