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Anticancer Effects of BRD4 Inhibitor in Epithelial Ovarian Cancer
Yeorae Kim1, Wook-Ha Park1, Dong-Hoon Suh1,2
1Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, 82 Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam 13620, Republic of Korea.
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.
Insights
This study shows OPT-0139, a bromodomain inhibitor (BRD4), effectively treats ovarian cancer by reducing cell growth and promoting apoptosis. It also overcomes chemoresistance, offering a promising new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Bromodomain inhibitors are investigated for cancer therapy.
- The role of bromodomain-containing proteins (BRDs) in ovarian cancer requires further clarification.
- Chemoresistance is a significant challenge in treating ovarian cancer.
Purpose of the Study:
- To evaluate the antitumor efficacy of OPT-0139, a novel drug designed to overcome chemoresistance in ovarian cancer.
- To elucidate the mechanism of action of OPT-0139, focusing on its effects on bromodomain and extra-terminal domain 4 (BRD4) and c-Myc.
- To assess the potential of OPT-0139 as a monotherapy and in combination with cisplatin for ovarian cancer treatment.
Main Methods:
- Utilized human ovarian cancer cell lines (SKOV3, OVCAR3) and a mouse xenograft model.
- Assessed cell viability and proliferation using MTT and ATP assays.
- Determined cell cycle arrest and apoptosis via flow cytometry.
- Quantified gene and protein expression of BRD4, c-Myc, and apoptosis-related molecules using RT-PCR, real-time PCR, and Western blot.
Main Results:
- OPT-0139 significantly inhibited ovarian cancer cell viability and proliferation.
- The drug induced cell cycle arrest and apoptosis in vitro.
- In vivo studies showed OPT-0139 reduced tumor growth, volume, and weight, with notable changes in BRD4-related gene expression.
- Combination therapy with cisplatin enhanced apoptosis and suppressed tumor growth more effectively than monotherapy.
Conclusions:
- OPT-0139 demonstrates significant antitumor activity in ovarian cancer models by inhibiting proliferation, reducing viability, arresting the cell cycle, and inducing apoptosis.
- OPT-0139 acts as a BRD4 inhibitor, suggesting its potential as a targeted therapy for ovarian cancer.
- Combination therapy with cisplatin may offer an improved treatment strategy for ovarian cancer, overcoming chemoresistance.
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