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The Protein Phosphatase 2A Inhibitor LB100 Sensitizes Ovarian Carcinoma Cells to Cisplatin-Mediated Cytotoxicity.
MedLine Citation:
PMID:  25376608     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Despite early positive response to platinum-based chemotherapy, the majority of ovarian carcinomas develop resistance and progress to fatal disease. Protein phosphatase 2A (PP2A) is a ubiquitous phosphatase involved in the regulation of DNA damage response and cell cycle checkpoint pathways. Recent studies have shown that LB100, a small molecule inhibitor of PP2A, sensitizes cancer cells to radiation-mediated DNA damage. We hypothesized that LB100 could sensitize ovarian cancer cells to cisplatin treatment. We performed in vitro studies in SKOV-3, OVCAR-8, and PEO1, 4, and 6 ovarian cancer lines to assess cytotoxicity potentiation, cell-death mechanism(s), cell cycle regulation, and DNA damage response signaling. In vivo studies were conducted in an intraperitoneal metastatic mouse model using SKOV-3/f-Luc cells. LB100 sensitized ovarian carcinoma lines to cisplatin-mediated cell death. Sensitization LB100 was mediated by abrogation of cell cycle arrest induced by cisplatin. Loss of the cisplatin-induced checkpoint correlated with decreased Wee1 expression, increased cdc2 activation, and increased mitotic entry (p-histone H3). As a result of its inhibition of PP2A, LB100 also induced constitutive hyperphosphorylation of DNA damage response proteins (BRCA1, Chk2, γH2AX), altered the chronology and persistence of JNK activation, and modulated the expression of 14-3-3 binding sites. In vivo, cisplatin sensitization via LB100 significantly enhanced tumor growth inhibition and prevented disease progression after treatment cessation. Our results suggest that LB100 sensitizes ovarian cancer cells to cisplatin in vitro and in vivo by modulation of the DNA damage response pathway and cell cycle checkpoint abrogation.
Authors:
Ki-Eun Chang; Bih-Rong Wei; James P Madigan; Matthew D Hall; R Mark Simpson; Zhengping Zhuang; Michael M Gottesman
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-11-5
Journal Detail:
Title:  Molecular cancer therapeutics     Volume:  -     ISSN:  1538-8514     ISO Abbreviation:  Mol. Cancer Ther.     Publication Date:  2014 Nov 
Date Detail:
Created Date:  2014-11-7     Completed Date:  -     Revised Date:  2014-11-8    
Medline Journal Info:
Nlm Unique ID:  101132535     Medline TA:  Mol Cancer Ther     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2014, American Association for Cancer Research.
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