Efficacy of inhibition of BAD Ser99 phosphorylation by a novel small molecule in cisplatin resistant ovarian cancer

Field: Pharmacology, Toxicology and Pharmaceutics (Life Sciences)

Event Abstract Back to Event Efficacy of inhibition of BAD Ser99 phosphorylation by a novel small molecule in cisplatin resistant ovarian cancer Yanxin Wang1* 1 National University of Singapore, Singapore Background Human BAD is a pro-apoptotic Bcl-2 family member, whose apoptotic functions can be inactivated through phosphorylation of specific residues including Ser99. Clinically, BAD phosphorylation has been reported to indicate poor survival and cisplatin resistance in ovarian cancer patients. Methods NPB, a novel small molecule which specifically inhibits BAD Ser99 phosphorylation, has been developed in our laboratory. Cell function assays performed include Alamar Blue cell viability assay, caspase3/7 assay, PI-Annexin V apoptosis assay, and 3D growth in Matrigel. The CI values are calculated using Chou-Talalay method. The cancer stem cell-like cell population was examined by ALDEFLOUR and sphere formation assays. Results The level of BAD Ser99 phosphorylation is negatively correlated with cisplatin sensitivity in a panel of ovarian cancer cell lines and it is increased upon acute cisplatin treatment in ovarian cancer cells. The inhibition of BAD Ser99 phosphorylation by NPB alone increased apoptosis, decreased anchorage-independent growth of both parental and cisplatin resistant ovarian cancer cells, with the combination of NPB and cisplatin showing a synergistic effect. An upstream BAD kinase, AKT has also been reported to mediate cisplatin resistance. Correspondingly, the combination of NPB and AKT inhibitor AZD5363 exhibited strong synergistic effects in both parental and cisplatin resistant cell lines. Both the phosphorylation of BAD and its upstream kinase AKT was increased in this CSC-like population. NPB treatment alone was observed to decrease the CSC-like population, while the combination of AZD5363 and NPB produced a synergistic decrease in the CSC-like population. Conclusion NPB, as a novel inhibitor of BAD Ser99 phosphorylation, can potentially be used in combination with cisplatin as a therapy for naïve ovarian cancer patients to increase cisplatin sensitivity. Furthermore, the combination of NPB and AKT inhibitor AZD5363 is a potential therapeutic approach in the treatment of cisplatin resistant ovarian cancer. Keywords: Bad phosphorylation, cisplatin resistance, ovarian cancer, NPB, Akt inhibitor Conference: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”, Putrajaya, Malaysia, 3 Dec - 5 Feb, 2019. Presentation Type: Speed Presentation Topic: Cancer Citation: Wang Y (2019). Efficacy of inhibition of BAD Ser99 phosphorylation by a novel small molecule in cisplatin resistant ovarian cancer. Front. Pharmacol. Conference Abstract: International Conference on Drug Discovery and Translational Medicine 2018 (ICDDTM '18) “Seizing Opportunities and Addressing Challenges of Precision Medicine”. doi: 10.3389/conf.fphar.2018.63.00013 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 07 Nov 2018; Published Online: 17 Jan 2019. * Correspondence: Ms. Yanxin Wang, National University of Singapore, Singapore, Singapore, wangyanxin98@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Yanxin Wang Google Yanxin Wang Google Scholar Yanxin Wang PubMed Yanxin Wang Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.