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

Purpose: 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. Experimental Design: 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 μmol/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.

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

“…1B and Dataset S2). This observation is consistent with previous studies reporting the activation of ER-stress-related genes such as GADD34 and CHOP in cells treated with Nelfinavir (20,21,26,27). To get more insight on the type of response engaged by Nelfinavir, we compared this signature with a dataset dissecting the ER-stress response in mouse embryonic fibroblasts (MEFs) (28).…”

“…(17,19). It was proposed that ER stress contributes to their antineoplastic activity (20)(21)(22). However, a detailed characterization of the stress responses triggered by the HIV-PIs has not been reported.…”

Radiation-induced autophagy in normal and cancer cells: Towards novel cytoprotection and radio-sensitization policies?

“…84,85 Nelfinavir, a lead HIV protease inhibitor, induces caspase-dependent apoptosis, endoplasmic reticulum stress and autophagy in non-small cell lung carcinoma cell lines. 86 The authors suggest that autophagy is a cellular response that mitigates nelfinavir-induced death and can be activated after ER stress to promote survival. 86 On the other hand, magnolol induces autophagic cell death but not apoptosis in H460 via the upregulation of PTEN and further downregulation of the mTOR pathway.…”

AIM2 inflammasome is activated by pharmacological disruption of nuclear envelope integrity

“…Beyond their broad use as anti-HIV drugs, these molecules display beneficial HIV-unrelated functions, antimalaria, antituberculosis, and antitumor properties (20). At the cellular level, the HIV-PIs trigger an atypical ER stress-like transcriptional response that relies mostly on the activation of the integrated stress response (19,21). However, the exact nature of the stress response engaged by these drugs is poorly understood, and its possible contribution to inflammation has not been investigated.…”