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BET 抑制剂与化疗联合使用可协同抑制 NSCLC 细胞的生长。

BET inhibitors combined with chemotherapy synergistically inhibit the growth of NSCLC cells.

机构信息

Department of Pain Management, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China.

Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu 211100, P.R. China.

出版信息

Oncol Rep. 2021 May;45(5). doi: 10.3892/or.2021.8021. Epub 2021 Mar 24.

Abstract

The bromodomain and extra‑terminal domain (BET) family proteins are essential epigenetic regulators in lung cancer. However, BET inhibitors have not had the anticipated therapeutic efficacy. Combined treatment using BET inhibitors along with other drugs had favorable therapeutic effects but the underlying molecular mechanisms remain elusive. The aim of the present study was to investigate the antineoplastic effects and mechanisms of a combination of a BET inhibitor and paclitaxel or cisplatin in non‑small cell lung cancer (NSCLC). By using the online Kaplan‑Meier plotter, it was revealed that increased mRNA levels of several BET protein‑coding genes were associated with poor prognosis in NSCLC. SRB assay results revealed that pharmaceutical or genetic targeting of BET proteins suppressed the growth of NSCLC cells. Inhibition of BET protein expression, in combination with the use of chemotherapeutic drugs such as paclitaxel and cisplatin, further restrained NSCLC cell growth in a synergistic manner. Mechanistically, this combination of suppression of BET expression and chemotherapeutic treatment blocked NSCLC cell growth by inhibiting autophagy and promoting apoptosis, which were revealed by both western blot and ELISA results. The present findings revealed a new rationale for using a combination of BET inhibitors with chemotherapy in NSCLC treatment.

摘要

溴结构域和末端结构域(BET)家族蛋白是肺癌中重要的表观遗传调节剂。然而,BET 抑制剂并未产生预期的治疗效果。BET 抑制剂与其他药物联合使用具有良好的治疗效果,但潜在的分子机制仍不清楚。本研究旨在探讨 BET 抑制剂联合紫杉醇或顺铂治疗非小细胞肺癌(NSCLC)的抗肿瘤作用及其机制。通过使用在线 Kaplan-Meier plotter 分析,结果显示几种 BET 蛋白编码基因的 mRNA 水平升高与 NSCLC 的预后不良相关。SRB 检测结果表明,药物或基因靶向 BET 蛋白可抑制 NSCLC 细胞的生长。抑制 BET 蛋白表达,联合使用化疗药物如紫杉醇和顺铂,以协同方式进一步抑制 NSCLC 细胞生长。从机制上讲,这种 BET 表达抑制与化疗联合应用通过抑制自噬和促进细胞凋亡来阻止 NSCLC 细胞生长,Western blot 和 ELISA 结果均证实了这一点。本研究结果为 BET 抑制剂联合化疗治疗 NSCLC 提供了新的理论依据。

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