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Apatinib combined with olaparib induces ferroptosis via a p53-dependent manner in ovarian cancer

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Abstract

Objective

PARP inhibitors combined with antiangiogenic drugs have been reported to improve outcomes in BRCA wild-type ovarian cancer patients, the mechanism of the combination is unclear. In this study, we explored the mechanism of apatinib combined with olaparib in the treatment of ovarian cancer.

Methods

In this study, human ovarian cancer cell lines A2780 and OVCAR3 were used as experimental objects, and the expression of ferroptosis-related protein GPX4 after treatment with apatinib and olaparib was detected by Western blot. The SuperPred database was used to predict the target of the combined action of apatinib and olaparib, and the predicted results were verified by Western blot experiment to explore the mechanism of ferroptosis induced by apatinib and olaparib.

Results

Apatinib combined with olaparib-induced ferroptosis in p53 wild-type cells, and p53 mutant cells developed drug resistance. The p53 activator RITA sensitized drug-resistant cells to ferroptosis induced by apatinib combined with olaparib. Apatinib combined with olaparib-induced ferroptosis via a p53-dependent manner in ovarian cancer. Further studies showed that apatinib combined with olaparib-induced ferroptosis by inhibiting the expression of Nrf2 and autophagy, thereby inhibiting the expression of GPX4. The Nrf2 activator RTA408 and the autophagy activator rapamycin rescued the combination drug-induced ferroptosis.

Conclusion

This discovery revealed the specific mechanism of ferroptosis induced by apatinib combined with olaparib in p53 wild-type ovarian cancer cells and provided a theoretical basis for the clinical combined use of apatinib and olaparib in p53 wild-type ovarian cancer patients.

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Data availability

The datasets of this study are available from the corresponding author on reasonable request.

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Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Author notes

  1. Wang Yue and Gu Yupeng contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Department of Medical Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China

    Wang Yue, Gu Yupeng & Jiang Kui

  2. Department of Occupational and Environmental Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China

    Cao Jun

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  1. Wang Yue
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  2. Gu Yupeng
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  3. Cao Jun
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  4. Jiang Kui
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Contributions

CJ and JK designed the study. GY performed the statistical analysis. WY and GY performed the experiments. WY wrote the manuscript. The authors read and approved the final manuscript.

Corresponding authors

Correspondence to Cao Jun or Jiang Kui.

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Yue, W., Yupeng, G., Jun, C. et al. Apatinib combined with olaparib induces ferroptosis via a p53-dependent manner in ovarian cancer. J Cancer Res Clin Oncol 149, 8681–8689 (2023). https://doi.org/10.1007/s00432-023-04811-1

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  • DOI: https://doi.org/10.1007/s00432-023-04811-1

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