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  2. Endogenous production of ω-3 polyunsaturated fatty acids mitigates cisplatin-induced myelosuppression by regulating NRF2-MDM2-p53 signaling pathway

Endogenous production of ω-3 polyunsaturated fatty acids mitigates cisplatin-induced myelosuppression by regulating NRF2-MDM2-p53 signaling pathway

  • Free Radic Biol Med. 2023 Mar 9;S0891-5849(23)00103-X. doi: 10.1016/j.freeradbiomed.2023.03.005.
Qihua Xu 1 Zongmeng Zhang 1 Minyi Tang 1 Chaofeng Xing 1 Hansi Chen 1 Kexin Zheng 1 Zhenggang Zhao 1 Sujin Zhou 1 Allan Zijian Zhao 1 Fanghong Li 2 Yunping Mu 3
Affiliations

Affiliations

  • 1 The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, PR China.
  • 2 The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, PR China. Electronic address: fli@gdut.edu.cn.
  • 3 The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, PR China. Electronic address: muyunping2018@gdut.edu.cn.
Abstract

Cisplatin is a chemotherapy medication used to treat a wide range of cancers. A common side effect of cisplatin is myelosuppression. Research suggests that oxidative damages are strongly and consistently related to myelosuppression during cisplatin treatment. ω-3 polyunsaturated fatty acids (PUFAs) can enhance the antioxidant capacity of cells. Herein, we investigated the protective benefit of endogenous ω-3 PUFAs on cisplatin-induced myelosuppression and the underlying signaling pathways using a transgenic mfat-1 mouse model. The expression of mfat-1 gene can increase endogenous levels of ω-3 PUFAs by enzymatically converting ω-6 PUFAs. Cisplatin treatment reduced peripheral blood cells and bone marrow nucleated cells, induced DNA damage, increased the production of Reactive Oxygen Species, and activated p53-mediated Apoptosis in bone marrow (BM) cells of wild-type mice. In the transgenics, the elevated tissue ω-3 PUFAs rendered a robust preventative effect on these cisplatin-induced damages. Importantly, we identified that the activation of NRF2 by ω-3 PUFAs could trigger an antioxidant response and inhibit p53-mediated Apoptosis by increasing the expression of MDM2 in BM cells. Thus, endogenous ω-3 PUFAs enrichment can strongly prevent cisplatin-induced myelosuppression by inhibiting oxidative damage and regulating the NRF2-MDM2-p53 signaling pathway. Elevation of tissue ω-3 PUFAs may represent a promising treatment strategy to prevent the side effects of cisplatin.

Keywords

Cisplatin; Myelosuppression; NRF2-MDM2-p53; Oxidative damages; Transgenic mfat-1 mice; ω-3 polyunsaturated fatty acids.

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