Xu Junfen, Shen Yuanming, Wang Conghui, Tang Sangsang, Hong Shiyuan, Lu Weiguo, Xie Xing, Cheng Xiaodong
Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
Zhejiang University School of Medicine, Hangzhou, 310058, China.
Cell Death Discov. 2021 Sep 22;7(1):259. doi: 10.1038/s41420-021-00638-2.
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.
聚（腺苷二磷酸 - 核糖）聚合酶（PARP）抑制剂在患有BRCA1/2突变或同源重组（HR）缺陷的卵巢癌患者中显示出生存益处，但在HR功能正常的患者中疗效有限。另一种药物，三氧化二砷（ATO）或含砷药物（RIF），通过诱导DNA损伤发挥抗肿瘤作用。在此，我们研究了PARP抑制剂与砷化合物在HR功能正常的卵巢癌中的联合治疗效果。尼拉帕利、奥拉帕利或氟唑帕利与ATO联合治疗显著抑制了肿瘤细胞活力和集落形成。药物治疗还通过同时或序贯给药诱导了两种HR功能正常的卵巢癌细胞系SKOV3和CAOV3的细胞增殖协同抑制、DNA损伤以及细胞凋亡加速。这些协同效应的潜在机制表现为裂解型PARP/总PARP比值显著增加以及p-AKT/总AKT比值降低。同样，奥拉帕利与RIF联合在小鼠异种移植模型中协同抑制了肿瘤生长。总之，砷化合物极大地使HR功能正常的卵巢癌细胞对PARP抑制剂敏感，我们的研究结果为这种联合疗法在HR功能正常的卵巢癌患者中的临床治疗开发提供了证据。
