Abstract
Abstract Background: BRCA1 plays an important role in DNA damage and repair, homologous recombination, cell-cycle regulation, and apoptosis. BRCA-mutated ovarian cancer often presents at an advanced stage, however, patients have shown improved responses with platinum-based chemotherapy versus sporadic cases. In spite of this, most patients will develop a recurrence and eventually succumb to the disease. Preclinical studies are currently investigating natural compounds and their analogs for tumor-directed targets in ovarian cancer cell models. The aim of this study is to investigate whether the STAT3 inhibitor HO-3867, a novel curcumin analog, has a therapeutic effect on BRCA1-mutated ovarian cancer. Methods: Expression of STAT family proteins, cell cycle, apoptotic and DNA repair proteins were evaluated via western blot on BRCA- mutated and non-mutated ovarian cancer cell lines. Cell viability and proliferation were analyzed with MTT and clonogenic assays. Cell cycle analysis and apoptosis assays were performed using flow cytometry and Annexin V staining. Reactive oxygen species (ROS) staining was performed using immunofluoresence. Finally, STAT3 overexpression or suppression experiments were performed using transfected wild-type STAT3 cDNA and STAT3 siRNA, respectively. Results: Our novel agent, HO-3867, and a commercial STAT3 inhibitor, STATIC, significantly inhibited BRCA-mutated cancer cells in vitro, in a dose-dependent manner. HO-3867 induced G2/M arrest with increased expression of p53 and p21 and with decreased cdk5 and cyclin D1 expression. BRCA-mutated cells treated with HO-3867 exhibited an increased induction of apoptosis with elevated levels of cleaved caspase-3, caspase-7, and PARP. Tyrosine-phosphorylated STAT3 (pTyr705) exhibited higher expression levels in BRCA-mutated cancer cells compared with other STAT proteins. Furthermore, treatment of these cells with HO-3867 resulted in decreased expression of pTyr705 and other DNA repair proteins. In addition, HO-3867 treatment induced more ROS in BRCA-mutated cells compared with wild-type cells, with no increased induction in benign ovarian surface epithelial cells. Furthermore, we confirmed that the over-expression of STAT3 cDNA provides resistance to HO-3867 induction of apoptosis. Conclusion: Our results show that HO-3867, a potential STAT3 inhibitor, may be effective in the treatment of BRCA-mutated ovarian cancer, although continued studies are needed to elucidate the exact mechanism of action. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4723. doi:1538-7445.AM2012-4723
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
