title: Nelfinavir, A lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo.
abstract: OBJECTIVE
  The development of new cancer drugs is slow and costly. HIV protease inhibitors are Food and Drug Administration approved for HIV patients. Because these drugs cause toxicities that can be associated with inhibition of Akt, an emerging target in cancer, we assessed the potential of HIV protease inhibitors as anticancer agents.
  
  
  METHODS
  HIV protease inhibitors were screened in vitro using assays that measure cellular proliferation, apoptotic and nonapoptotic cell death, endoplasmic reticulum (ER) stress, autophagy, and activation of Akt. Nelfinavir was tested in non-small cell lung carcinoma (NSCLC) xenografts with biomarker assessment.
  
  
  RESULTS
  Three of six HIV protease inhibitors, nelfinavir, ritonavir, and saquinavir, inhibited proliferation of NSCLC cells, as well as every cell line in the NCI60 cell line panel. Nelfinavir was most potent with a mean 50% growth inhibition of 5.2 micromol/L, a concentration achievable in HIV patients. Nelfinavir caused two types of cell death, caspase-dependent apoptosis and caspase-independent death that was characterized by induction of ER stress and autophagy. Autophagy was protective because an inhibitor of autophagy increased nelfinavir-induced death. Akt was variably inhibited by HIV protease inhibitors, but nelfinavir caused the greatest inhibition of endogenous and growth factor-induced Akt activation. Nelfinavir decreased the viability of a panel of drug-resistant breast cancer cell lines and inhibited the growth of NSCLC xenografts that was associated with induction of ER stress, autophagy, and apoptosis.
  
  
  CONCLUSIONS
  Nelfinavir is a lead HIV protease inhibitor with pleiotropic effects in cancer cells. Given its wide spectrum of activity, oral availability, and familiarity of administration, nelfinavir is a Food and Drug Administration-approved drug that could be repositioned as a cancer therapeutic.
authors.affiliation: Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20889, USA.
authors.forename: Joell J
authors.initials: JJ
authors.lastname: Gills
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Lopiccolo
authors.forename: Junji
authors.initials: J
authors.lastname: Tsurutani
authors.forename: Robert H
authors.initials: RH
authors.lastname: Shoemaker
authors.forename: Carolyn J M
authors.initials: CJ
authors.lastname: Best
authors.forename: Mones S
authors.initials: MS
authors.lastname: Abu-Asab
authors.forename: Jennifer
authors.initials: J
authors.lastname: Borojerdi
authors.forename: Noel A
authors.initials: NA
authors.lastname: Warfel
authors.forename: Erin R
authors.initials: ER
authors.lastname: Gardner
authors.forename: Matthew
authors.initials: M
authors.lastname: Danish
authors.forename: M Christine
authors.initials: MC
authors.lastname: Hollander
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kawabata
authors.forename: Maria
authors.initials: M
authors.lastname: Tsokos
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Dennis
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D020169:Caspases / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D005260:Female; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019888:Nelfinavir / Q000493:pharmacokinetics / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism