title: Inhibition of Akt Enhances the Chemopreventive Effects of Topical Rapamycin in Mouse Skin.
abstract: The PI3Kinase/Akt/mTOR pathway has important roles in cancer development for multiple tumor types, including UV-induced nonmelanoma skin cancer. Immunosuppressed populations are at increased risk of aggressive cutaneous squamous cell carcinoma (SCC). Individuals who are treated with rapamycin (sirolimus, a classical mTOR inhibitor) have significantly decreased rates of developing new cutaneous SCCs compared with those that receive traditional immunosuppression. However, systemic rapamycin use can lead to significant adverse events. Here, we explored the use of topical rapamycin as a chemopreventive agent in the context of solar-simulated light (SSL)-induced skin carcinogenesis. In SKH-1 mice, topical rapamycin treatment decreased tumor yields when applied after completion of 15 weeks of SSL exposure compared with controls. However, applying rapamycin during SSL exposure for 15 weeks, and continuing for 10 weeks after UV treatment, increased tumor yields. We also examined whether a combinatorial approach might result in more significant tumor suppression by rapamycin. We validated that rapamycin causes increased Akt (S473) phosphorylation in the epidermis after SSL, and show for the first time that this dysregulation can be inhibited in vivo by a selective PDK1/Akt inhibitor, PHT-427. Combining rapamycin with PHT-427 on tumor prone skin additively caused a significant reduction of tumor multiplicity compared with vehicle controls. Our findings indicate that patients taking rapamycin should avoid sun exposure, and that combining topical mTOR inhibitors and Akt inhibitors may be a viable chemoprevention option for individuals at high risk for cutaneous SCC.
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona. Department of Pharmacology, The University of Arizona, Tucson, Arizona. sdickinson@uacc.arizona.edu.
authors.forename: Sally E
authors.initials: SE
authors.lastname: Dickinson
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Janda
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Jane
authors.initials: J
authors.lastname: Criswell
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Karen
authors.initials: K
authors.lastname: Blohm-Mangone
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Erik R
authors.initials: ER
authors.lastname: Olson
authors.affiliation: Department of Medical Imaging, The University of Arizona, Tucson, Arizona.
authors.forename: Zhonglin
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Medical Imaging, The University of Arizona, Tucson, Arizona.
authors.forename: Christy
authors.initials: C
authors.lastname: Barber
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia.
authors.forename: Emanuel F
authors.initials: EF
authors.lastname: Petricoin
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia.
authors.forename: Valerie S
authors.initials: VS
authors.lastname: Calvert
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona. Department of Medicine, The University of Arizona, Tucson, Arizona.
authors.forename: Janine
authors.initials: J
authors.lastname: Einspahr
authors.affiliation: Arizona Water Science Center, U.S. Geological Survey, Tucson, Arizona.
authors.forename: Jesse E
authors.initials: JE
authors.lastname: Dickinson
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona. Department of Medicine, The University of Arizona, Tucson, Arizona.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Stratton
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona. Department of Medicine, The University of Arizona, Tucson, Arizona.
authors.forename: Clara
authors.initials: C
authors.lastname: Curiel-Lewandrowski
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Kathylynn
authors.initials: K
authors.lastname: Saboda
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, The Hormel Institute, The University of Minnesota, Austin, Minnesota.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, The Hormel Institute, The University of Minnesota, Austin, Minnesota.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona. Department of Medicine, The University of Arizona, Tucson, Arizona.
authors.forename: David S
authors.initials: DS
authors.lastname: Alberts
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona. Department of Medicine, The University of Arizona, Tucson, Arizona. Department of Cellular and Molecular Medicine, The University of Arizona, Tucson, Arizona.
authors.forename: G
authors.initials: G
authors.lastname: Timothy Bowden
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D015153:Blotting, Western; D005260:Female; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D008812:Mice, Hairless; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000528:radiation effects; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013449:Sulfonamides / Q000494:pharmacology; D013472:Sunlight / Q000009:adverse effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D000903:Antibiotics, Antineoplastic; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; D013830:Thiadiazoles; C550093:4-dodecyl-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C546842:MTOR protein, human