Repositioning HIV protease inhibitors as cancer therapeutics

Abstract

Purpose of review: Although designed to target only the HIV protease, HIV protease inhibitors induce toxicities in patients such as insulin resistance and lipodystrophy that suggest that protease inhibitors have other targets in mammalian cells. Akt controls insulin signaling and is an important target in cancer, but no Akt inhibitors are approved as cancer therapeutics. These observations have prompted the study of HIV protease inhibitors as inhibitors of Akt and possible cancer therapeutics. This review will highlight the latest advances in repositioning HIV protease inhibitors as cancer therapeutics.

Recent findings: Although protease inhibitors can inhibit Akt activation and the proliferation of over 60 cancer cell lines, as well as improve sensitivity to radiation or chemotherapy, these effects do not always correlate with Akt inhibition. Other important processes, such as the induction of endoplasmic reticulum stress, appear critical to the biological activity of protease inhibitors. These impressive and surprising preclinical data have prompted clinical testing of nelfinavir as a lead HIV protease inhibitor in cancer patients.

Summary: Although mechanisms of action for the antitumor effects of HIV protease inhibitors are complex, their broad spectrum of activity, minimal toxicity, and wide availability make protease inhibitors ideal candidates for repositioning as cancer therapeutics.

Figure 1. Activation of Akt promotes cellular survival through multiple mechanisms

Akt inhibits apoptosis by phosphorylation of many substrates, including 1. the FoxO subfamily of forkhead family transcription factors that inhibits the transcription of pro-apoptotic genes, 2. pro-apoptotic proteins such as BAD and caspase 9, which inactivates them, and 3. IKK, which indirectly increases the activity of NF-κB and stimulates the transcription of pro-survival genes. Cell cycle progression is promoted by phosphorylation of the cdk inhibitor p21, which is subsequently cleared via the proteasome. Phosphorylation of MDM2 by Akt leads to increased ubiquitinylation of p53 and increased cleared by the proteasome.

Figure 2. Potential sites of action of HIV PIs

The black Xs represent possible sites of action of protease inhibitors. The inhibition of Akt phosphorylation results in a loss translation of the pro-survival genes and a loss in the inhibitory phosphorylation of the pro-apoptotic proteins caspase 9 and BAD. p21 and p53 may induce cell cycle arrest. Inhibition of the proteasome results in the accumulation of unfolded proteins and the unfolded protein response. To permit cell recovery, a global decrease in protein synthesis or autophagy may follow.