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.
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.
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.
aMedical Oncology Branch, Center for Cancer Research, National Cancer Institute, USA
bDepartment of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
Correspondence to Phillip A. Dennis, NCI/Navy Medical Oncology, Room 5101 Building 8, 8901 Wisconsin Ave, Bethesda, MD 20899, USA Tel: +1 301 496 0929; fax: +1 301 496 0047; e-mail: firstname.lastname@example.org