title: Apoptosis is augmented in high-grade serous ovarian cancer by the combined inhibition of Bcl-2/Bcl-xL and PARP.
abstract: The aim of our study was to evaluate possible synergistic cytotoxic effects of the combination treatment with the BH3-mimetic ABT-263 and the PARP inhibitor BMN 673 in high-grade serous ovarian cancer (HGSOC) cells using clinically achievable concentrations of each drug. In vitro cytotoxic effects of ABT-263 and BMN 673 were assessed by XTT assay in three HGSOC cell lines: OVCAR3, OVCAR8, and OV90 cells. Combination index values and synergy/antagonism volumes were used to determine synergy. The drug effects on DNA damage accumulation, cell cycle progression, apoptosis induction, and expression levels of Bcl-2 family proteins were examined to dissect molecular mechanisms. The combination treatment synergistically decreased cell viability in a concentration- and time-dependent manner in all cell lines; combination index values were <0.9 and synergy/antagonism volumes were >100 after 72 h of treatment. Clinically achievable concentrations of ABT-263 2 µM and BMN 673 25 nM were used to investigate mechanisms. No increase in γ-H2AX foci formation was observed with addition of ABT-263 to BMN 673 treatment. The combination treatment increased the sub-G1 and Annexin V-positive cell populations after 48 h compared with the control and each monotherapy. It also induced greater caspase-3/7 activity and PARP cleavage. ABT-263 alone and in combination with BMN 673 induced expression levels of Bim, a pro-apoptotic protein. In conclusion, the ABT-263 and BMN 673 combination resulted in synergistic cytotoxic effects against HGSOC cells through greater induction of apoptosis. This may be a novel therapeutic strategy for HGSOC.
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Takuhei
authors.initials: T
authors.lastname: Yokoyama
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Elise C
authors.initials: EC
authors.lastname: Kohn
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Brill
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Jung-Min
authors.initials: JM
authors.lastname: Lee