Open Access

Apoptosis is augmented in high-grade serous ovarian cancer by the combined inhibition of Bcl-2/Bcl-xL and PARP

  • Authors:
    • Takuhei Yokoyama
    • Elise C. Kohn
    • Ethan Brill
    • Jung-Min Lee
  • View Affiliations

  • Published online on: March 15, 2017     https://doi.org/10.3892/ijo.2017.3914
  • Pages: 1064-1074
  • Copyright: © Yokoyama et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.
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April-2017
Volume 50 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Yokoyama T, Kohn EC, Brill E and Lee J: Apoptosis is augmented in high-grade serous ovarian cancer by the combined inhibition of Bcl-2/Bcl-xL and PARP. Int J Oncol 50: 1064-1074, 2017
APA
Yokoyama, T., Kohn, E.C., Brill, E., & Lee, J. (2017). Apoptosis is augmented in high-grade serous ovarian cancer by the combined inhibition of Bcl-2/Bcl-xL and PARP. International Journal of Oncology, 50, 1064-1074. https://doi.org/10.3892/ijo.2017.3914
MLA
Yokoyama, T., Kohn, E. C., Brill, E., Lee, J."Apoptosis is augmented in high-grade serous ovarian cancer by the combined inhibition of Bcl-2/Bcl-xL and PARP". International Journal of Oncology 50.4 (2017): 1064-1074.
Chicago
Yokoyama, T., Kohn, E. C., Brill, E., Lee, J."Apoptosis is augmented in high-grade serous ovarian cancer by the combined inhibition of Bcl-2/Bcl-xL and PARP". International Journal of Oncology 50, no. 4 (2017): 1064-1074. https://doi.org/10.3892/ijo.2017.3914