Abstract
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. 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. 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. 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.
Highlights
The development of new cancer drugs is slow and costly
To determine if HIV protease inhibitors had potential as cancer therapeutics, we screened six Food and Drug Administration (FDA)-approved HIV protease inhibitors in cell proliferation assays using two non ^ small cell lung carcinoma (NSCLC) cell lines (A549 and H157; Fig. 1A)
Ritonavir, and saquinavir inhibited growth of two NSCLC cell lines, we assessed the spectrum of activity of these HIV protease inhibitors by screening them in the NCI60 cell line panel that contains 60 cell lines derived from nine different tumor types
Summary
The development of new cancer drugs is slow and costly. HIV protease inhibitors are Food and Drug Administration approved for HIV patients. To accelerate the availability of pathway inhibitors for clinical testing, we screened six clinically approved HIV protease inhibitors and found that three inhibited growth in a wide variety of cancer cell types at concentrations that have been achieved in patients infected with HIV. The most potent HIV protease inhibitor, nelfinavir, exerted pleiotropic biochemical and cellular effects that included induction of endoplasmic reticulum (ER) stress, autophagy, and apoptosis in vitro and in vivo. These studies provide a rationale to test nelfinavir as an anticancer agent and suggest that drug repositioning could complement traditional drug development in oncology
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