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Cited by 20Ovarian cancer diagnosis and treatmentCell death mechanisms and regulationCancer Cells and Metastasis

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Pharmacological Inhibition of BAD Ser99 Phosphorylation Enhances the Efficacy of Cisplatin in Ovarian Cancer by Inhibition of Cancer Stem Cell-like Behavior

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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·ACS Pharmacology & Translational Science
DOI 10.1021/acsptsci.0c00064PMC PMC7737213
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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 IC50 in 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.

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Crossref · 10.1021/acsptsci.0c00064

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  • The simultaneous use of NPB and cisplatin significantly inhibited the growth of EOC xenografts to a greater extent than NPB or cisplatin alone, partly by diminishing the population of stem cell-like cells in cisplatin-resistant EOC.

    “The simultaneous use of NPB and cisplatin significantly inhibited the growth of EOC xenografts to a greater extent than NPB or cisplatin alone [32], partly by diminishing the population of stem cell-like cells in cisplatin-resistant EOC.”

    From Combining Mitomycin C with inhibition of BAD phosphorylation enhances apoptotic cell death in advanced cervical cancer (2024) · cites this paper as [32]

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Metadata

Authors
Wang, Y., Chiou, Y.-S., Chong, Q.-Y., Zhang, M., Rangappa, K. S., Ma, L., Zhu, T., Kumar, A. P., Huang, R. Y.-J., Pandey, V., Basappa, & Lobie, P. E.
Affiliations
  • National University of Singapore (SG)
  • Tsinghua–Berkeley Shenzhen Institute (CN)
  • Nankai University (CN)
  • University of Mysore (IN)
  • Shenzhen Bay Laboratory (CN)
  • University of Science and Technology of China (CN)
Corresponding author
  • Basappa
  • Lobie, Peter E.
ORCID
Venue
ACS Pharmacology & Translational Science
Publisher
American Chemical Society (ACS)
Published
2020-10-09
Volume
3
Issue
6
Pages
1083-1099
ISSN
2575-9108 (ISSN-L)
DOI
10.1021/acsptsci.0c00064
PMC
PMC7737213
OpenAlex
W3091995211
Cited by
20
References
3
Citations by year
2026: 4 · 2025: 7 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 3
FWCI
1.54
Type
journal article
Language
en
Open access
Licence
Locations
  • ACS Pharmacology & Translational Science (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • National University of Singapore (submittedVersion)
  • MyPrints@UOM (Mysore University Library) (submittedVersion)
Funders
  • National Medical Research Council (R-713-000-163-511)
  • Ministry of Education - Singapore
  • TBSI
  • Shenzhen Development and Reform Commission Subject Construction Project ([2017]1434)
  • VGST, GOK, India
  • Shenzhen Bay Laboratory
Topics
  • Health Sciences › Medicine › Oncology › Ovarian cancer diagnosis and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
ovarian cancer, cisplatin resistance, cancer stem cells, apoptosis, small molecule inhibitors, combination therapy, AKT inhibitors, AZD5363, chemoresistance, drug synergy

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