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.