The protein phosphatase 2A inhibitor LB100 sensitizes ovarian carcinoma cells to cisplatin-mediated cytotoxicity.

Therapeutic Approaches

Abstract

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 (DDR) 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 DDR 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 via 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). LB100 also induced constitutive hyperphosphorylation of DDR proteins (BRCA1, Chk2, and 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 DDR pathway and cell-cycle checkpoint abrogation.

Authors

Chang, Ki-Eun; Wei, Bih-Rong; Madigan, James P; Hall, Matthew; Simpson, R Mark; Zhuang, Zhengping; Gottesman, Michael M;

Keywords

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols
  • Bicyclo Compounds, Heterocyclic/ administration & dosage
  • Bicyclo Compounds, Heterocyclic/ pharmacology
  • Cell Cycle/ drug effects
  • Cell Line, Tumor
  • Cisplatin/ administration & dosage
  • Drug Synergism
  • Female
  • Gene Expression Regulation, Neoplastic/ drug effects
  • Humans
  • Mice
  • Ovarian Neoplasms/ drug therapy
  • Piperazines/ administration & dosage
  • Piperazines/ pharmacology
  • Protein Phosphatase 2/ antagonists & inhibitors
  • Signal Transduction/ drug effects
  • Treatment Outcome
  • Xenograft Model Antitumor Assays

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