Abstract

BackgroundShort-term starvation (STS) has gradually been confirmed as a treatment method that synergistically enhances the effect of chemotherapy on malignant tumours. In clinical applications, there are still some limitations of poly (ADP-ribose) polymerase inhibitors (PARPi), including understanding their effectiveness and side effects. Here, we sought to investigate the effect and mechanism of the combined use of STS and niraparib in the treatment of ovarian cancer.MethodsIn in vitro experiments, SKOV3 and A2780 ovarian cancer cells were treated with STS and niraparib alone or in combination. Cell viability was assessed with CCK-8, and cell cycle, apoptosis, DNA damage repair and autophagy were examined to explore the molecular mechanisms. Akt and mTOR inhibitors were used to examine any changes in DNA damage repair levels. Xenograft animal models were treated with STS and niraparib, and HE staining and immunohistochemistry were performed to examine the effects.ResultsThe combined use of STS and niraparib inhibited cell proliferation and increased apoptosis more than niraparib application alone. In addition, compared with the niraparib group, the STS + niraparib group had increased G2/M arrest, DNA damage and autophagy, which indicated that STS pretreatment enhanced the cytotoxicity of niraparib. In animal experiments, STS did not affect the growth of transplanted tumours, but the combined treatment synergistically enhanced the cytotoxicity of niraparib. In in vivo experiments, STS did not affect the growth of transplanted tumours, but the combined treatment synergistically enhanced the cytotoxicity of niraparib and reduced the small intestinal side effects caused by niraparib chemotherapy.ConclusionSTS pretreatment can synergistically enhance the cytotoxicity of niraparib. STS + niraparib is a potentially effective strategy in the maintenance therapy of ovarian cancer.

Highlights

  • Epithelial ovarian cancer (EOC), as the most lethal gynaecological malignancy, shows a higher mortality rate than other common gynaecological malignancies, such asPoly (ADP-ribose) polymerase inhibitors (PARPi) are expected to be an effective drug for the treatmentZhi et al Cancer Cell International (2022) 22:18 of ovarian cancer by targeting DNA repair

  • For the Cell Counting Kit (CCK)-8 assay, SKOV3 and A2780 cells were incubated in 0–40 μM niraparib for 24 or 48 h (Fig. 1b), and the results indicated that after niraparib treatment, the proliferation of SKOV3 and A2780 cells decreased significantly in dose- and time-dependent manners

  • Both SKOV3 and A2780 cells were incubated in 0 μM, 2.5 μM, 5 μM, and 10 μM niraparib for 48 h, and western blotting was performed to analyse the protein expression of PARP-1

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Summary

Introduction

Epithelial ovarian cancer (EOC), as the most lethal gynaecological malignancy, shows a higher mortality rate than other common gynaecological malignancies, such asPoly (ADP-ribose) polymerase inhibitors (PARPi) are expected to be an effective drug for the treatmentZhi et al Cancer Cell International (2022) 22:18 of ovarian cancer by targeting DNA repair. (ADP-ribose) polymerase inhibitors (PARPi) are expected to be an effective drug for the treatment. Niraparib is an approved oral PARPi for the maintenance treatment of ovarian cancer. PARPi was initially used to treat ovarian cancer patients with BRCA1 mutations. Regardless of the occurrence of BRCA mutations, the effectiveness of PARPi for the maintenance treatment of ovarian cancer has been verified in many clinical studies [6, 7]. Overcoming drug resistance is one of the keys to maintenance treatment of ovarian cancer, and combination strategies are a scientifically rational way to target alternative DNA repair pathways to improve PARPi sensitivity. There are still some limitations of poly (ADP-ribose) polymerase inhibitors (PARPi), including understanding their effectiveness and side effects. We sought to investigate the effect and mechanism of the combined use of STS and niraparib in the treatment of ovarian cancer

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