Arsenic compound sensitizes homologous recombination proficient ovarian cancer to PARP inhibitors

Junfen Xu; Yuanming Shen; Conghui Wang; Sangsang Tang; Shiyuan Hong; Weiguo Lu; Xing Xie; Xiaodong Cheng

doi:10.1038/s41420-021-00638-2

Arsenic compound sensitizes homologous recombination proficient ovarian cancer to PARP inhibitors

Cell Death Discov. 2021 Sep 22;7(1):259. doi: 10.1038/s41420-021-00638-2.

Authors

Junfen Xu^#¹, Yuanming Shen^#¹, Conghui Wang², Sangsang Tang², Shiyuan Hong³, Weiguo Lu^{1

4

5}, Xing Xie¹, Xiaodong Cheng⁶

Affiliations

¹ Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
² Zhejiang University School of Medicine, Hangzhou, 310058, China.
³ Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, China.
⁴ Center of Uterine Cancer Diagnosis & Therapy of Zhejiang Province, Hangzhou, 310006, Zhejiang, China.
⁵ Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
⁶ Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China. chengxd@zju.edu.cn.

^# Contributed equally.

Abstract

The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors show survival benefits in ovarian cancer patients with BRCA1/2 mutation or homologous recombination (HR) deficiency, but only limited efficacy in HR-proficient ones. Another drug, arsenic trioxide (ATO) or arsenic drug (RIF), exerts antitumor effects via inducing DNA damage. Here, we investigated the combined therapeutic effects of the PARP inhibitors and the arsenic compound in HR-proficient ovarian cancer. The combined treatment of niraparib, olaparib, or fluazolepali with ATO showed a significant suppression in tumor cell viability and colony formation. The drug treatment also induced synergistic inhibition of cell proliferation and DNA damage, and acceleration of cell apoptosis in two HR-proficient ovarian cancer cell lines SKOV3 and CAOV3, either by simultaneous or sequential administration. The mechanism underlying these synergistic effects were reflected by the significantly increased ratio of cleaved-PARP/total PARP and decreased ratio of p-AKT/total AKT. Consistently, the combination of olaparib with RIF synergistically reduced the tumor growth in mouse xenograft models. In conclusion, the arsenic compound greatly sensitizes HR-proficient ovarian cancer cells to the PARP inhibitors, and our findings provide an evidence for the clinical treatment development of this combination in HR-proficient ovarian cancer patients.