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Sodium cantharidinate, a novel anti-pancreatic cancer agent that activates functional p53

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Abstract

Despite the use of many types of chemotherapies for pancreatic cancer, optimal efficacy has not been obtained so far. Pancreatic cancer shows a high incidence of TP53 mutations, inactivating its tumor suppressor activity. In this study, we identified sodium cantharidinate as a novel, potential anti-pancreatic cancer agent that activates p53 function. Sodium cantharidinate reduced the viability of pancreatic cancer cells, including the human primary pancreatic cancer cells, PANC-1, AsPC-1, SW1990 and BXPC-3, in a dose-dependent manner. Sodium cantharidinate induced apoptosis and DNA damage of pancreatic cancer cells. Furthermore, proteome-wide sequencing analysis detected a marked perturbation in p53 signaling pathway on PANC-1 cells upon sodium cantharidinate. Consistent with the previous results, sodium cantharidinate treatment decreased Bcl-2 and mitochondrial cytochrome-c protein expression, as well as phosphorylation of MDM2; meanwhile, it increased the levels of cleaved-caspase-3, cleaved-caspase-9, cleaved-PARP, Bax, and phosphorylated p53, thus inducing the apoptosis of pancreatic cancer cells. The p53-activating effect of sodium cantharidinate was strongly abrogated by treatment with TP53-targeting shRNA. Moreover, sodium cantharidinate inhibited neoplasm growth via the JAK2-STAT3 pathway, which was inhibited by shRNA-TP53 and triggered by combination with gemcitabine. Combination therapy indicated that sodium cantharidinate and gemcitabine synergistically reduced ex vivo and in vivo growth of pancreatic neoplasm. Further docking studies revealed the different binding fates of sodium cantharidinate to activate wild-type p53 function. Thus, sodium cantharidinate could be a potential agent with promising anti-pancreatic cancer efficacy.

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Acknowledgements

This work was supported by the National Key R&D Program of China (2019YFC1711000 to P.L.), the National Natural Science Foundation of China (81772566 to J.L.), and in part by the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (SKLNMZZCX201820 to X.X.), and the “Double First-Class” University Project (CPU2018GF04 to X.X.).

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  1. Contributed equally to this work

Authors and Affiliations

  1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China

    Xiaoxiao Liu, Li Zhang, Pyone Myat Thu, Wenjian Min, Peng Yang, Ping Li & Xiaojun Xu

  2. Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, 210009, China

    Xiaojun Xu

  3. Department of Pancreatic Surgery, Huashan Hospital, Fudan University, Shanghai, 200040, China

    Ji Li

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  1. Xiaoxiao Liu
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  2. Li Zhang
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Correspondence to Ping Li or Xiaojun Xu.

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Liu, X., Zhang, L., Thu, P.M. et al. Sodium cantharidinate, a novel anti-pancreatic cancer agent that activates functional p53. Sci. China Life Sci. 64, 1295–1310 (2021). https://doi.org/10.1007/s11427-019-1753-3

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