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

Cancers

Bhavishya Sarma¹  David Schrama¹  Roland Houben¹  Laura Angerer¹  Christian Adam¹  Christoph Willmes¹  Thibault Kervarrec²  JürgenC. Becker³ 

[1] Department of Dermatology, University Hospital Würzburg, 97082 Würzburg, Germany;Department of Pathology, Centre Hospitalier Universitaire De Tours, INRA UMR 1282 BIP, 37200 Tours, France;Department of Translational Skin Cancer Research, Dermatology, University Hospital Essen, 45147 Essen, Germany;

关键词: artesunate;    Merkel cell carcinoma;    MCC;    polyomavirus;    ferroptosis;   

DOI  :  10.3390/cancers12040919

来源: DOAJ

【 摘 要 】

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 β-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.

【 授权许可】

Unknown