The HSP70 modulator MAL3-101 inhibits Merkel cell carcinoma.
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.
Department of Dermatology, University Hospital of Würzburg, Würzburg, Germany.
Christian
C
Adam
Department of Dermatology, University Hospital of Würzburg, Würzburg, Germany.
Anne
A
Baeurle
Departments of Chemistry and Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Jeffrey L
JL
Brodsky
Departments of Chemistry and Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Peter
P
Wipf
Division of General Dermatology, Medical University of Graz, Graz, Austria.
David
D
Schrama
Division of General Dermatology, Medical University of Graz, Graz, Austria.
Jürgen Christian
JC
Becker
Department of Dermatology, University Hospital of Würzburg, Würzburg, Germany.
Roland
R
Houben
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015266:Carcinoma, Merkel Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011120:Polyomavirus / Q000235:genetics / Q000378:metabolism*; D027601:Polyomavirus Infections / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D014412:Tumor Virus Infections / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000957:Antigens, Viral, Tumor; D000970:Antineoplastic Agents; D018840:HSP70 Heat-Shock Proteins; D009363:Neoplasm Proteins