Phenethyl Isothiocyanate Enhances the Cytotoxic Effects of PARP Inhibitors in High-Grade Serous Ovarian Cancer Cells.

Yaxun Jia,Pixu Liu,Hailing Cheng,Min Wang,Xiaolin Sang,Kui Jiang,Jingchun Gao

doi:10.3389/fonc.2021.812264

Abstract

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 H2O2-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 N-Acetyl-L-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.

Highlights

High-grade serous ovarian cancer (HGSOC) is among the most common and aggressive histologic subtypes and is associated with poor survival [1, 2]
A substantial body of preclinical and clinical studies have demonstrated that inhibition of PARP1 induces synthetic lethality in HGSOC with homologous recombination repair (HRR) deficiencies caused by deleterious BRCA1/2 mutations or BRCAness [5–7]
The current study aims to investigate whether phenethyl isothiocyanate (PEITC), a known reactive oxygen species (ROS)-generating agent [17–19], enhances the cytotoxic effects of PARP inhibitor (PARPi) in HGSOC and cervical cancer

Summary

Introduction

High-grade serous ovarian cancer (HGSOC) is among the most common and aggressive histologic subtypes and is associated with poor survival [1, 2]. 50% of HGSOC harbor defects in the homologous recombination repair (HRR) pathways [3]. PEITC Enhances PARPi Cytotoxicity (PARP1/2) is required to repair DNA single-strand breaks, and PARP1 involved in the repair of DNA replication fork damage and double-strand breaks [4]. A substantial body of preclinical and clinical studies have demonstrated that inhibition of PARP1 induces synthetic lethality in HGSOC with HRR deficiencies caused by deleterious BRCA1/2 mutations or BRCAness [5–7]. PARP inhibitor (PARPi)-based therapies are a standard of care for HGSOC patients. Despite PARPi therapies have shown encouraging results, HGSOC tumors frequently become resistant. The development of effective combinatorial strategies to treat this hardly curable disease is urgently needed

Methods

Results

Conclusion