Jia Yaxun, Wang Min, Sang Xiaolin, Liu Pixu, Gao Jingchun, Jiang Kui, Cheng Hailing
Cancer Institute, Dalian Key Laboratory of Molecular Targeted Cancer Therapy, The Second Hospital of Dalian Medical University, Dalian, China.
Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
Front Oncol. 2022 Jan 26;11:812264. doi: 10.3389/fonc.2021.812264. eCollection 2021.
While PARP inhibitor (PARPi) therapies have shown promising results in the treatment of high-grade serous ovarian cancer (HGSOC) harboring homologous recombination deficiencies, primary resistance to PARPi frequently occurs and even initial responders may eventually become resistant. Therefore, the development of novel effective combinatorial strategies to treat HGSOC is urgently needed. Here, we report that HO-induced oxidative stress sensitized HGSOC cells to PARPi BMN 673. Furthermore, Phenethyl isothiocyanate (PEITC) as a ROS-inducing agent significantly enhanced the cytotoxic effects of BMN 673. Mechanistically, combined use of PEITC and BMN 673 resulted in ROS overproduction and accumulation, enhanced DNA damage, G2/M arrest and apoptosis, all of which were significantly reversed by the ROS scavenger -Acetyl--cysteine. We also showed that while PEITC did not further enhance the ability of BMN 673 on PARP1 trapping in HGSOC cells, the therapeutic effects of the PEITC/BMN 673 combination were at least in part dependent on the presence of PARP1. Importantly, the PEITC/BMN 673 combination potently abrogated the growth of HGSOC tumor spheroids and patient-derived organoid models of HGSOC and cervical cancer. Our findings provide a basis for further investigation of the utility of PARPi combination regimen in HGSOC and cervical cancer through ROS-mediated mechanisms.
虽然聚（ADP-核糖）聚合酶抑制剂（PARPi）疗法在治疗存在同源重组缺陷的高级别浆液性卵巢癌（HGSOC）方面已显示出有前景的结果，但对PARPi的原发性耐药经常发生，甚至最初的反应者最终也可能产生耐药。因此，迫切需要开发新的有效联合策略来治疗HGSOC。在此，我们报告HO诱导的氧化应激使HGSOC细胞对PARPi BMN 673敏感。此外，异硫氰酸苯乙酯（PEITC）作为一种ROS诱导剂显著增强了BMN 673的细胞毒性作用。从机制上讲，PEITC和BMN 673联合使用导致ROS过量产生和积累，增强了DNA损伤、G2/M期阻滞和凋亡，而ROS清除剂乙酰半胱氨酸可显著逆转所有这些情况。我们还表明，虽然PEITC没有进一步增强BMN 673在HGSOC细胞中捕获PARP1的能力，但PEITC/BMN 673联合疗法的治疗效果至少部分依赖于PARP1的存在。重要的是，PEITC/BMN 673联合用药有力地抑制了HGSOC肿瘤球体以及HGSOC和宫颈癌患者来源类器官模型的生长。我们的研究结果为通过ROS介导的机制进一步研究PARPi联合方案在HGSOC和宫颈癌中的效用提供了基础。
