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 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.Cancers 2020, 12, 919 2 of 15 cells [6], and subsequent studies confirmed that approximately 80% of all MCC cases are associated with MCPyV [7]. Importantly, the integration patterns suggest that clonal expansion of the tumor cells occurs after MCPyV integration sustaining the assumption that viral proteins are causal for tumorigenesis [6,8,9]. Moreover, in MCPyV-positive MCC cells, expression of the viral oncoproteins small and Large T-antigen (sT and LT) can be detected, and these proteins are essential for growth of the tumor cells [10,11] qualifying them as potential therapeutic targets.The five-year overall survival rate for patients with MCC is only about 40%, although the relative survival rate (compared to an age-and sex-matched population) is 54% [12]. Primary MCCs are excised by surgery, and adjuvant radiotherapy of the primary tumor location and the lymph node region is recommended [13]. Until recently, the metastatic disease was treated preferentially with various, not-standardized chemotherapeutic regimens, all of which could not improve survival of the patients significantly [14]. Recently, however, antibodies targeting the immune suppressive protein programmed cell death protein 1 (PD-1) or its ligand PD-L1 have demonstrated high response rates of 56 in first-line and 32% in second-line treatment, respectively for patients with stage IV disease [15,16]. Indeed, the PD-L1 targeting antibody Avelumab was the first treatment for metastatic MCC approved both in the US and European Union [17]. Importantly, data avail...

Merkel Cell Polyomavirus and Merkel Cell Carcinoma

“…However, some molecules not specific for MCPyV show anti-viral activity in cell culture and xenograft models. The malaria drug artesunate reduces growth and survival of VP-MCC cells in vitro and VP-MCC tumors in a xenograft mouse model, but had no or little effect on primary fibroblasts, melanoma cell lines, and non-classical VN-MCC cell lines [ 259 ]. Artesunate down-regulated expression of LT, but only in one VP-MCC cell line was the sensitivity towards artesunate reduced upon knockdown of LT expression.…”

Progress on the study of the anticancer effects of artesunate (Review)

“…ART Chauhan et al (138) found that ART induced ROS production and subsequent cell death in a receptor-interacting protein 1-dependent manner in human renal carcinoma. ART exerted a potent antiproliferative effect on polyomavirus-positive Merkel cell carcinoma (MCC) cells with good overall tolerance and induced ferroptosis (139). In addition, ART also significantly suppressed the growth of established MCC tumors in xenotransplanted mice, suggesting that ART may be used for the treatment of MCC (138).…”

Artesunate Inhibits the Growth Behavior of Docetaxel-Resistant Prostate Cancer Cells

“…Artemisinin, extracted from Artemisia annua (Sweet Wormwood), was developed in Traditional Chinese Medicine to treat malaria (14). Artesunate (ART) (Figure 1A), derived from artemisinin, exhibits remarkable anti-cancer activity towards a broad variety of tumor cell lines (15,16), including prostate carcinoma (17)(18)(19). Moreover, ART exhibits antiinflammatory properties, thereby preventing tissue destruction induced by carcinogens in vivo (20).…”