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Cellular and Molecular Biology

Capecitabine induces hand-foot syndrome through elevated thymidine phosphorylase-mediated locoregional toxicity and GSDME-driven pyroptosis that can be relieved by tipiracil

British Journal of Cancer volume 128, pages 219–231 (2023)Cite this article

Subjects

Abstract

Background

Hand-foot syndrome (HFS) is a serious dose-limiting cutaneous toxicity of capecitabine-containing chemotherapy, leading to a deteriorated quality of life and negative impacts on chemotherapy treatment. The symptoms of HFS have been widely reported, but the precise molecular and cellular mechanisms remain unknown. The metabolic enzyme of capecitabine, thymidine phosphorylase (TP) may be related to HFS. Here, we investigated whether TP contributes to the HFS and the molecular basis of cellular toxicity of capecitabine.

Methods

TP-/- mice were generated to assess the relevance of TP and HFS. Cellular toxicity and signalling mechanisms were assessed by in vitro and in vivo experiments.

Results

TP-/- significantly reduced capecitabine-induced HFS, indicating that the activity of TP plays a critical role in the development of HFS. Further investigations into the cellular mechanisms revealed that the cytotoxicity of the active metabolite of capecitabine, 5-DFUR, was attributed to the cleavage of GSDME-mediated pyroptosis. Finally, we demonstrated that capecitabine-induced HFS could be reversed by local application of the TP inhibitor tipiracil.

Conclusion

Our findings reveal that the presence of elevated TP expression in the palm and sole aggravates local cell cytotoxicity, further explaining the molecular basis underlying 5-DFUR-induced cellular toxicity and providing a promising approach to the therapeutic management of HFS.

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Fig. 1: Catabolic pathway and the pharmacokinetics of capecitabine.
Fig. 2: High expression of thymidine phosphorylase in the palm and planta contributed to capecitabine-induced HFS.
Fig. 3: GSDME-mediated pyroptosis-induced HFS in HaCaT cells.
Fig. 4: TPI protected against 5-DFUR-induced pyroptosis.
Fig. 5: Topical application of TPI gel relieved capecitabine-induced HFS in a mouse model.
Fig. 6: Topical application of TPI gel does not affect the antitumor effect of capecitabine.

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Data availability

All data associated with this study are present in the paper or the Supplementary Materials.

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Acknowledgements

We acknowledge Yi Lin and Yushuo Zhang for helpful scientific discussion and manuscript editing. We are thankful to the Shanghai Cancer Institute for the technical platform.

Funding

This work was supported by the Youth Thousand Talents Programme of China, start-up grants from the Shanghai Jiao Tong University (WF220408211). This work was also supported by the grants from the State Key Laboratory of Onco- genes and Related Genes (90-17-02) and from the Interdisciplinary Programme of Shanghai Jiao Tong University (YG2017MS18).

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Authors and Affiliations

  1. School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China

    Bingxue Yang

  2. School of Pharmacy and School of Biomedical Engineering, Shanghai Jiao Tong University, 200240, Shanghai, China

    Xinran Xie, Dazhao Lv, Jiajun Hu, Yuyun Chen, Zhaoyu Wu, Shuyue Luo & Shiyi Zhang

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Contributions

BY and XX performed the experiments and wrote the paper. YL, SL, ZW and YC performed some of the in vitro experiments. DL aided in some animal experiments. JH performed xenograft tumour model. BY analysed the data. SZ supervised all experiments. SZ reviewed and edited the manuscript. All authors approved the paper.

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Correspondence to Shiyi Zhang.

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Yang, B., Xie, X., Lv, D. et al. Capecitabine induces hand-foot syndrome through elevated thymidine phosphorylase-mediated locoregional toxicity and GSDME-driven pyroptosis that can be relieved by tipiracil. Br J Cancer 128, 219–231 (2023). https://doi.org/10.1038/s41416-022-02039-3

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