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.
为开发溴结构域抑制剂作为癌症治疗手段，相关研究已取得进展。含溴结构域蛋白（BRD）在卵巢癌等疾病中影响的亚通路机制尚不明确。本研究验证了一种新型药物OPT-0139在克服化疗耐药性治疗卵巢癌中的抗肿瘤效应。通过建立SKOV3和OVCAR3人卵巢癌细胞的小鼠异种移植模型，采用MTT法和ATP检测评估细胞活力与增殖能力，流式细胞术测定细胞周期阻滞与凋亡情况，并运用RT-PCR、实时荧光定量PCR及Western blot技术检测BRD4、c-Myc表达及凋亡相关分子变化。研究证实了OPT-0139在上皮性卵巢癌中的作用机制：该药物能显著降低细胞活力与增殖能力，诱导细胞凋亡与周期阻滞。在动物模型中观察到肿瘤生长、体积、重量及BRD4相关基因表达的显著改变，提示BRD4抑制剂具有抗肿瘤效应。与顺铂的联合治疗在体内外实验中均能促进细胞凋亡并抑制肿瘤生长。研究结果表明，BRD4抑制剂OPT-0139通过抑制细胞增殖、降低细胞活力、阻滞细胞周期并诱导细胞凋亡，有望成为治疗卵巢癌的潜在抗癌药物。
Anticancer Effects of BRD4 Inhibitor in Epithelial Ovarian Cancer
肿瘤(癌症)患者之家