Combination effect of poly (ADP-ribose) polymerase inhibitor and DNA demethylating agents for treatment of epithelial ovarian cancer

Jung In Shim, Ji Yoon Ryu, Soo Young Jeong, Young Jae Cho, Jung Joo Choi, Jae Ryoung Hwang, Ju Yeon Choi, Jason K. Sa, Jeong Won Lee

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Poly (ADP)-ribose polymerase inhibitors (PARPi) are effective clinical agents for treatment of epithelial ovarian cancer (EOC) harboring BRCA mutations as well as those without BRCA mutations. In this study, we evaluate the efficacy of combined PARPi and DNA methyltransferase inhibitor (DNMTi) in EOCs. Methods: Expression levels of DNMT1 and PARP1 proteins in EOC cells were assessed using western blot analysis and immunohistochemistry. To evaluate the effects of co-treatment of PARPi (olaparib) and DNMTi (5-azacitidine, 5-AZA), we performed cell proliferation, apoptosis, and wound-healing assays in EOC cells. In addition, we performed in vivo experiments using both cell-line and patient-derived xenograft (PDX) models of EOC. Results: The combination of olaparib and 5-AZA significantly inhibited cell proliferation and migration and induced apoptosis compared with olaparib or 5-AZA alone in EOC cell lines including A2780, HeyA8, A2780-CP20, and HeyA8-MDR. Moreover, in vivo experiments with this combination showed significantly decreased weight and nodule numbers of tumors in cell-line xenograft models with A2780 cells and a PDX model compared with control, olaparib, and 5-AZA groups. As a potential mechanism, the expression of intracellular reactive oxygen species (ROS) and its related proteins, including p-ERK, NRF2, p-p38, HO-1, and γH2AX, was affected in EOC cells. Conclusions: Co-treatment with PARPi and DNMTi had a significant anti-tumor effect in EOC cells. This combination might be a potential therapeutic strategy for EOCs.

Original languageEnglish
Pages (from-to)270-280
Number of pages11
JournalGynecologic Oncology
Volume165
Issue number2
DOIs
Publication statusPublished - 2022 May

Keywords

  • 5-AZA
  • Animal model
  • Epithelial ovarian cancer
  • Olaparib
  • Patient-derived xenograft

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynaecology

Fingerprint

Dive into the research topics of 'Combination effect of poly (ADP-ribose) polymerase inhibitor and DNA demethylating agents for treatment of epithelial ovarian cancer'. Together they form a unique fingerprint.

Cite this