The HSP70 modulator MAL3-101 inhibits Merkel cell carcinoma

• Published in: PloS one 2014-04, Vol.9 (4), p.e92041
• Main Authors: Adam, Christian, Baeurle, Anne, Brodsky, Jeffrey L, Wipf, Peter, Schrama, David, Becker, Jürgen Christian, Houben, Roland
• Format: Article
• Language: English
• Subjects: Analysis; Animals; Anticancer properties; Antigen T (large); Antigens; Antigens, Viral, Tumor - genetics; Antigens, Viral, Tumor - metabolism; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Biology; Biology and Life Sciences; Biotechnology; Cancer; Cancer therapies; Carcinoma, Merkel Cell - drug therapy; Carcinoma, Merkel Cell - genetics; Carcinoma, Merkel Cell - metabolism; Carcinoma, Merkel Cell - virology; Care and treatment; Cell cycle; Cell Line, Tumor; Cell survival; Cell Transformation, Viral - drug effects; Cell Transformation, Viral - genetics; Chemotherapy; Coding; Deoxyribonucleic acid; Dermatology; Diagnosis; DNA; Fibroblasts; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Heat shock; Heat shock proteins; Hospitals; Hsc70 protein; HSP70 Heat-Shock Proteins - antagonists & inhibitors; HSP70 Heat-Shock Proteins - biosynthesis; HSP70 Heat-Shock Proteins - genetics; Hsp70 protein; Humans; Isoforms; Medical prognosis; Medical research; Medicine and Health Sciences; Merkel cell carcinoma; Mice; Mice, Inbred NOD; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Physical Sciences; Polyomavirus - genetics; Polyomavirus - metabolism; Polyomavirus Infections - drug therapy; Polyomavirus Infections - genetics; Polyomavirus Infections - metabolism; RNA; Skin; Skin cancer; Skin diseases; Tumor Virus Infections - drug therapy; Tumor Virus Infections - genetics; Tumor Virus Infections - metabolism; Tumor Virus Infections - pathology; Tumors; Viruses; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0092041

Merkel Cell Carcinoma (MCC) is a rare and highly aggressive neuroendocrine skin cancer for which no effective treatment is available. MCC represents a human cancer with the best experimental evidence for a causal role of a polyoma virus. Large T antigens (LTA) encoded by polyoma viruses are oncoproteins, which are thought to require support of cellular heat shock protein 70 (HSP70) to exert their transforming activity. Here we evaluated the capability of MAL3-101, a synthetic HSP70 inhibitor, to limit proliferation and survival of various MCC cell lines. Remarkably, MAL3-101 treatment resulted in considerable apoptosis in 5 out of 7 MCC cell lines. While this effect was not associated with the viral status of the MCC cells, quantitative mRNA expression analysis of the known HSP70 isoforms revealed a significant correlation between MAL3-101 sensitivity and HSC70 expression, the most prominent isoform in all cell lines. Moreover, MAL3-101 also exhibited in vivo antitumor activity in an MCC xenograft model suggesting that this substance or related compounds are potential therapeutics for the treatment of MCC in the future.