title: Topically applied Hsp90 inhibitor 17AAG inhibits UVR-induced cutaneous squamous cell carcinomas.
abstract: We present here that heat-shock protein 90 (Hsp90) inhibitor 17-(allylamino)-17-demethoxygeldanamycin (17AAG), when topically applied to mouse skin, inhibits UVR-induced development of cutaneous squamous cell carcinoma (SCC). In these experiments, DMSO:acetone (1:40 v/v) solution of 17AAG (500 nmol) was applied topically to mouse skin in conjunction with each UVR exposure (1.8 kJ m(-2)). The UVR source was Kodacel-filtered FS-40 sun lamps (approximately 60% UVB and 40% UVA). In independent experiments with three separate mouse lines (SKH-1 hairless mice, wild-type FVB, and protein kinase C epsilon (PKCɛ)-overexpressing transgenic FVB mice), 17AAG treatment increased the latency and decreased both the incidence and multiplicity of UVR-induced SCC. Topical 17AAG alone or in conjunction with UVR treatments elicited neither skin nor systemic toxicity. 17AAG-caused inhibition of SCC induction was accompanied by a decrease in UVR-induced (1) hyperplasia, (2) Hsp90β-PKCɛ interaction, and (3) expression levels of Hsp90β, Stat3, pStat3Ser727, pStat3Tyr705, pAktSer473, and matrix metalloproteinase (MMP). The results presented here indicate that topical Hsp90 inhibitor 17AAG is effective in prevention of UVR-induced epidermal hyperplasia and SCC. One may conclude from the preclinical data presented here that topical 17AAG may be useful for prevention of UVR-induced inflammation and cutaneous SCC either developed in UVR-exposed or organ transplant population.
authors.affiliation: Department of Human Oncology, Wisconsin Institutes for Medical Research, Paul P. Carbone Comprehensive Cancer, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Anupama
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Human Oncology, Wisconsin Institutes for Medical Research, Paul P. Carbone Comprehensive Cancer, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Ashok
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Human Oncology, Wisconsin Institutes for Medical Research, Paul P. Carbone Comprehensive Cancer, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Sand
authors.affiliation: Department of Human Oncology, Wisconsin Institutes for Medical Research, Paul P. Carbone Comprehensive Cancer, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Bauer
authors.affiliation: Department of Human Oncology, Wisconsin Institutes for Medical Research, Paul P. Carbone Comprehensive Cancer, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Bilal Bin
authors.initials: BB
authors.lastname: Hafeez
authors.affiliation: Department of Human Oncology, Wisconsin Institutes for Medical Research, Paul P. Carbone Comprehensive Cancer, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Louise
authors.initials: L
authors.lastname: Meske
authors.affiliation: Department of Human Oncology, Wisconsin Institutes for Medical Research, Paul P. Carbone Comprehensive Cancer, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA. Electronic address: akverma@facstaff.wisc.edu.
authors.forename: Ajit K
authors.initials: AK
authors.lastname: Verma
mesh_terms: D000096:Acetone / Q000737:chemistry; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004817:Epidermis / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism* / Q000517:prevention & control; D051379:Mice; D009381:Neoplasms, Radiation-Induced / Q000378:metabolism* / Q000517:prevention & control; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D012867:Skin / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D014466:Ultraviolet Rays; D000096142:Cutaneous Malignant Melanoma
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; C490097:Hsp90b1 protein, mouse; D047029:Lactams, Macrocyclic; D000096:Acetone; C112765:tanespimycin; D051744:Protein Kinase C-epsilon; D020782:Matrix Metalloproteinases; D004121:Dimethyl Sulfoxide