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.
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.
Gills
Joell J
JJ
Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20889, USA.
Lopiccolo
Jaclyn
J
Tsurutani
Junji
J
Shoemaker
Robert H
RH
Best
Carolyn J M
CJ
Abu-Asab
Mones S
MS
Borojerdi
Jennifer
J
Warfel
Noel A
NA
Gardner
Erin R
ER
Danish
Matthew
M
Hollander
M Christine
MC
Kawabata
Shigeru
S
Tsokos
Maria
M
Figg
William D
WD
Steeg
Patricia S
PS
Dennis
Phillip A
PA
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