title: HIV protease inhibitor nelfinavir inhibits growth of human melanoma cells by induction of cell cycle arrest.
abstract: HIV protease inhibitors (HIV PI) are a class of antiretroviral drugs that are designed to target the viral protease. Unexpectedly, this class of drugs is also reported to have antitumor activity. In this study, we have evaluated the in vitro activity of nelfinavir, a HIV PI, against human melanoma cells. Nelfinavir inhibits the growth of melanoma cell lines at low micromolar concentrations that are clinically attainable. Nelfinavir promotes apoptosis and arrests cell cycle at G(1) phase. Cell cycle arrest is attributed to inhibition of cyclin-dependent kinase 2 (CDK2) and concomitant dephosphorylation of retinoblastoma tumor suppressor. We further show that nelfinavir inhibits CDK2 through proteasome-dependent degradation of Cdc25A phosphatase. Our results suggest that nelfinavir is a promising candidate chemotherapeutic agent for advanced melanoma, for which novel and effective therapies are urgently needed.
authors.affiliation: Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania Medical Center, 4 Silverstein, 3400 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mikochik
authors.forename: Jin H
authors.initials: JH
authors.lastname: Ra
authors.forename: Hanqin
authors.initials: H
authors.lastname: Lei
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Winkler
authors.forename: Francis R
authors.initials: FR
authors.lastname: Spitz
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D019888:Nelfinavir / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: D017320:HIV Protease Inhibitors; D016160:Retinoblastoma Protein; D051057:Proto-Oncogene Proteins c-akt; D051357:Cyclin-Dependent Kinase 2; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases; D019888:Nelfinavir