The Anti-Cancer Properties of the HIV Protease Inhibitor Nelfinavir

SIMPLE SUMMARY: To this day, cancer remains a medical challenge despite the development of cutting-edge diagnostic methods and therapeutics. Thus, there is a continual demand for improved therapeutic options for managing cancer patients. However, novel drug development requires decade-long time commitment and financial investments. Repurposing approved and market-available drugs for cancer therapy is a way to reduce cost and the timeframe for developing new therapies. Nelfinavir is an anti-infective agent that has extensively been used to treat acquired immunodeficiency syndrome (AIDS) in adult and pediatric patients. In addition to its anti-infective properties, nelfinavir has demonstrated potent off-target anti-cancer effects, suggesting that it could be a suitable candidate for drug repurposing for cancer. In this review, we systematically compiled the therapeutic benefits of nelfinavir against cancer as a single drug or in combination with chemoradiotherapy, and outlined the possible underlying mechanistic pathways contributing to the anti-cancer effects. ABSTRACT: Traditional cancer treatments may lose efficacy following the emergence of novel mutations or the development of chemoradiotherapy resistance. Late diagnosis, high-cost of treatment, and the requirement of highly efficient infrastructure to dispense cancer therapies hinder the availability of adequate treatment in low-income and resource-limited settings. Repositioning approved drugs as cancer therapeutics may reduce the cost and timeline for novel drug development and expedite the availability of newer, efficacious options for patients in need. Nelfinavir is a human immunodeficiency virus (HIV) protease inhibitor that has been approved and is extensively used as an anti-infective agent to treat acquired immunodeficiency syndrome (AIDS). Yet nelfinavir has also shown anti-cancer effects in in vitro and in vivo studies. The anti-cancer mechanism of nelfinavir includes modulation of different cellular conditions, such as unfolded protein response, cell cycle, apoptosis, autophagy, the proteasome pathway, oxidative stress, the tumor microenvironment, and multidrug efflux pumps. Multiple clinical trials indicated tolerable and reversible toxicities during nelfinavir treatment in cancer patients, either as a monotherapy or in combination with chemo- or radiotherapy. Since orally available nelfinavir has been a safe drug of choice for both adult and pediatric HIV-infected patients for over two decades, exploiting its anti-cancer off-target effects will enable fast-tracking this newer option into the existing repertoire of cancer chemotherapeutics.