Abstract
Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer associated with high mortality. Merkel cell polyomavirus (MCV), discovered in 2008, is associated with ~80% of MCC. The MCV large tumor (LT) oncoprotein upregulates the cellular oncoprotein survivin through its conserved retinoblastoma protein-binding motif. We confirm here that YM155, a survivin suppressor, is cytotoxic to MCV-positive MCC cells in vitro at nanomolar levels. Mouse survival was significantly improved for NOD-Scid-Gamma mice treated with YM155 in a dose and duration dependent manner for 3 of 4 MCV-positive MCC xenografts. One MCV-positive MCC xenograft (MS-1) failed to significantly respond to YM155, which corresponds with in vitro dose-response activity. Combination treatment of YM155 with other chemotherapeutics resulted in additive but not synergistic cell killing of MCC cell lines in vitro. These results suggest that survivin targeting is a promising therapeutic approach for most but not all MCV-positive MCCs.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / pharmacology
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Carcinoma, Merkel Cell / drug therapy
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Carcinoma, Merkel Cell / metabolism*
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Carcinoma, Merkel Cell / mortality
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Carcinoma, Merkel Cell / pathology
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Carcinoma, Merkel Cell / virology*
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Transformation, Viral* / genetics
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Disease Models, Animal
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Female
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Humans
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Imidazoles / administration & dosage
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Imidazoles / pharmacology
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Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism
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Merkel cell polyomavirus / genetics*
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Mice
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Naphthoquinones / administration & dosage
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Naphthoquinones / pharmacology
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Neoplasm Metastasis
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Polyomavirus Infections / complications
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Survivin
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Tumor Burden / drug effects
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Tumor Virus Infections / complications
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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BIRC5 protein, human
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Imidazoles
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Inhibitor of Apoptosis Proteins
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Naphthoquinones
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Survivin
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sepantronium