Olaparib synergizes with arsenic trioxide by promoting apoptosis and ferroptosis in platinum-resistant ovarian cancer
Sangsang Tang, Yuanming Shen, Xinyi Wei, Zhangjin Shen, Weiguo Lü, Junfen Xu
Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors are efficacious in treating platinum-sensitive ovarian cancer (OC), but demonstrate limited efficiency in patients with platinum-resistant OC. Thus, further investigations into combined strategies that enhance the response to PARP inhibitors (PARPi) in platinum-resistant OC are required. The present study aimed to investigate the combined therapy of arsenic trioxide (ATO) with olaparib, a common PARPi, and determine how this synergistic cytotoxicity works in platinum-resistant OC cells. Functional assays demonstrated that the combined treatment of olaparib with ATO significantly suppressed cell proliferation and colony formation, and enhanced DNA damage as well as cell apoptosis in A2780-CIS and SKOV3-CIS cell lines. Results of the present study also demonstrated that a combination of olaparib with ATO increased lipid peroxidation and eventually triggered ferroptosis. Consistently, the combined treatment synergistically suppressed tumor growth in mice xenograft models. Mechanistically, ATO in combination with olaparib activated the AMPK α pathway and suppressed the expression levels of stearoyl-CoA desaturase 1 (SCD1). Collectively, results of the present study demonstrated that treatment with ATO enhanced the effects of olaparib in platinum-resistant OC.