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Repositioning HIV protease inhibitors as cancer therapeutics

Bernstein, Wendy Ba,b; Dennis, Phillip Aa

Current Opinion in HIV and AIDS: November 2008 - Volume 3 - Issue 6 - p 666–675
doi: 10.1097/COH.0b013e328313915d
HIV protease inhibitors: Edited by Jon Schapiro and John Erickson

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.

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: dennisp@mail.nih.gov

© 2008 Lippincott Williams & Wilkins, Inc.