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BRD4抑制剂在上皮性卵巢癌中的抗癌作用

Anticancer Effects of BRD4 Inhibitor in Epithelial Ovarian Cancer.

作者信息

Kim Yeorae, Park Wook-Ha, Suh Dong-Hoon, Kim Kidong, No Jae-Hong, Kim Yong-Beom

机构信息

Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, 82 Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam 13620, Republic of Korea.

Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 103 Jongno-gu, Seoul 03080, Republic of Korea.

出版信息

Cancers (Basel). 2024 Feb 27;16(5):959. doi: 10.3390/cancers16050959.

Abstract

Efforts have been made to develop bromodomain inhibitors as cancer treatments. Sub-pathways, particularly in ovarian cancer, affected by bromodomain-containing protein (BRD) remain unclear. This study verified the antitumor effects of a new drug that can overcome OPT-0139-chemoresistance to treat ovarian cancer. A mouse xenograft model of human ovarian cancer cells, SKOV3 and OVCAR3, was used in this study. Cell viability and proliferation were assessed using MTT and ATP assays. Cell cycle arrest and apoptosis were determined using flow cytometry. BRD4 and c-Myc expression and apoptosis-related molecules were detected using RT-PCR and real-time PCR and Western blot. We confirmed the OPT-0139 effect and mechanism of action in epithelial ovarian cancer. OPT-0139 significantly reduced cell viability and proliferation and induced apoptosis and cell cycle arrest. In the mouse xenograft model, significant changes in tumor growth, volume, weight, and BRD4-related gene expression were observed, suggesting the antitumor effects of BRD4 inhibitors. Combination therapy with cisplatin promoted apoptosis and suppressed tumor growth in vitro and in vivo. Our results suggest OPT-0139, a BRD4 inhibitor, as a promising anticancer drug for the treatment of ovarian cancer by inhibiting cell proliferation, decreasing cell viability, arresting cell cycle, and inducing apoptosis.

摘要

人们已努力开发溴结构域抑制剂作为癌症治疗药物。受含溴结构域蛋白(BRD)影响的亚通路,尤其是在卵巢癌中的亚通路,仍不清楚。本研究验证了一种可克服OPT - 0139化疗耐药性以治疗卵巢癌的新药的抗肿瘤作用。本研究使用了人卵巢癌细胞SKOV3和OVCAR3的小鼠异种移植模型。使用MTT和ATP测定法评估细胞活力和增殖。使用流式细胞术确定细胞周期停滞和凋亡。使用RT - PCR、实时PCR和蛋白质印迹法检测BRD4和c - Myc表达以及凋亡相关分子。我们证实了OPT - 0139在上皮性卵巢癌中的作用效果和作用机制。OPT - 0139显著降低细胞活力和增殖,并诱导凋亡和细胞周期停滞。在小鼠异种移植模型中,观察到肿瘤生长、体积、重量以及BRD4相关基因表达的显著变化,提示BRD4抑制剂的抗肿瘤作用。顺铂联合治疗在体外和体内均促进凋亡并抑制肿瘤生长。我们的结果表明,BRD4抑制剂OPT - 0139通过抑制细胞增殖、降低细胞活力、使细胞周期停滞和诱导凋亡,有望成为治疗卵巢癌的抗癌药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/52c0/10930785/474edad4057c/cancers-16-00959-g001.jpg

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