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https://doi.org/10.1021/acsptsci.0c00064
Title: | Pharmacological Inhibition of BAD Ser99 Phosphorylation Enhances the Efficacy of Cisplatin in Ovarian Cancer by Inhibition of Cancer Stem Cell-like Behavior | Authors: | Wang, Yanxin Chiou, Yi-Shiou Chong, Qing-Yun Zhang, Mengyi Rangappa, Kanchuragoppal S Ma, Lan Zhu, Tao Kumar, Alan Prem Huang, Ruby Yun-Ju Pandey, Vijay Basappa Lobie, Peter E |
Keywords: | Science & Technology Life Sciences & Biomedicine Chemistry, Medicinal Pharmacology & Pharmacy BAD phosphorylation NPB ovarian cancer cisplatin resistance cancer stem cell PHASE-III TRIAL INTERGROUP TRIAL CARBOPLATIN-PACLITAXEL 1ST-LINE TREATMENT SURVIVAL PROTEIN MECHANISMS THERAPY DEATH DRUG |
Issue Date: | 11-Dec-2020 | Publisher: | AMER CHEMICAL SOC | Citation: | Wang, Yanxin, Chiou, Yi-Shiou, Chong, Qing-Yun, Zhang, Mengyi, Rangappa, Kanchuragoppal S, Ma, Lan, Zhu, Tao, Kumar, Alan Prem, Huang, Ruby Yun-Ju, Pandey, Vijay, Basappa, Lobie, Peter E (2020-12-11). Pharmacological Inhibition of BAD Ser99 Phosphorylation Enhances the Efficacy of Cisplatin in Ovarian Cancer by Inhibition of Cancer Stem Cell-like Behavior. ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE 3 (6) : 1083-1099. ScholarBank@NUS Repository. https://doi.org/10.1021/acsptsci.0c00064 | Abstract: | Platinum-based chemotherapy has been the standard treatment for ovarian cancer patients for approximately four decades. However, the prognosis of patients with advanced ovarian carcinoma remains dismal, mainly attributed to both dose-limiting toxicities of cisplatin and the high rate of chemo-resistant disease recurrence. Herein, both patient-derived and experimentally generated cisplatin-sensitive and -resistant ovarian cancer cell line models were used to delineate BADSer99 phosphorylation as an actionable target in ovarian cancer. BADSer99 phosphorylation was negatively associated with cisplatin sensitivity in ovarian cancer, and the inhibition of BADSer99 phosphorylation by point mutation induced apoptosis and reduced cisplatin IC50. In addition, BAD phosphorylation was also shown to be associated with cancer stem cell-like properties. Henceforth, a novel small molecule which inhibits BAD phosphorylation specifically at Ser99 (NPB) was utilized. NPB promoted apoptosis and reduced 3D growth of bulk cancer cells and inhibited cancer stem cell-like properties in both cisplatin-sensitive and -resistant ovarian cancer cells. The combination of cisplatin with NPB exhibited synergistic effects in vitro. NPB in combination with cisplatin also achieved an improved outcome compared to either monotreatment in vivo, including suppression of the cancer stem cell population, an effect not observed with cisplatin treatment. Furthermore, NPB exhibited strong synergistic effects with the AKT inhibitor AZD5363, and significantly reduced its IC50in cells resistant to cisplatin treatment. These findings identify BADSer99 phosphorylation as an actionable and pharmacologically relevant target to improve outcomes of cisplatin treated ovarian cancer. | Source Title: | ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE | URI: | https://scholarbank.nus.edu.sg/handle/10635/245936 | ISSN: | 2575-9108 | DOI: | 10.1021/acsptsci.0c00064 |
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