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Artesunate Affects T Antigen Expression and Survival of Virus-Positive Merkel Cell Carcinoma

Abstract : Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer with frequent viral etiology. Indeed, in about 80% of cases, there is an association with Merkel cell polyomavirus (MCPyV); the expression of viral T antigens is crucial for growth of virus-positive tumor cells. Since artesunate-a drug used to treat malaria-has been reported to possess additional anti-tumor as well as anti-viral activity, we sought to evaluate pre-clinically the effect of artesunate on MCC. We found that artesunate repressed growth and survival of MCPyV-positive MCC cells in vitro. This effect was accompanied by reduced large T antigen (LT) expression. Notably, however, it was even more efficient than shRNA-mediated downregulation of LT expression. Interestingly, in one MCC cell line (WaGa), T antigen knockdown rendered cells less sensitive to artesunate, while for two other MCC cell lines, we could not substantiate such a relation. Mechanistically, artesunate predominantly induces ferroptosis in MCPyV-positive MCC cells since known ferroptosis-inhibitors like DFO, BAF-A1, Fer-1 and beta-mercaptoethanol reduced artesunate-induced death. Finally, application of artesunate in xenotransplanted mice demonstrated that growth of established MCC tumors can be significantly suppressed in vivo. In conclusion, our results revealed a highly anti-proliferative effect of the approved and generally well-tolerated anti-malaria compound artesunate on MCPyV-positive MCC cells, suggesting its potential usage for MCC therapy.
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https://hal.inrae.fr/hal-02972827
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Submitted on : Thursday, October 22, 2020 - 2:33:00 PM
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Bhavishya Sarma, Christoph Willmes, Laura Angerer, Christian Adam, Jürgen Becker, et al.. Artesunate Affects T Antigen Expression and Survival of Virus-Positive Merkel Cell Carcinoma. Cancers, MDPI, 2020, 12 (4), 15 p. ⟨10.3390/cancers12040919⟩. ⟨hal-02972827⟩

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