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.

High-grade serous ovarian cancer (HGSOC) is a significant cause of mortality among women worldwide. Traditional treatment consists of platinum-based therapy; however, rapid development of platinum resistance contributes to lower life expectancy, warranting newer therapies to supplement the current platinum-based protocol. Repurposing market-available drugs as cancer therapeutics is a cost- and time-effective way to avail new therapies to drug-resistant patients. The anti-HIV agent nelfinavir (NFV) has shown promising toxicity against various cancers; however, its role against HGSOC is unknown. Here, we studied the effect of NFV against HGSOC cells obtained from patients along disease progression and carrying different sensitivities to platinum. NFV triggered, independently of platinum sensitivity, a dose-dependent reduction in the HGSOC cell number and viability, and a parallel increase in hypo-diploid DNA content. Moreover, a dose-dependent reduction in clonogenic survival of cells escaping the acute toxicity was indicative of long-term residual damage. In addition, dose- and time-dependent phosphorylation of H2AX indicated NFV-mediated DNA damage, which was associated with decreased survival and proliferation signals driven by the AKT and ERK pathways. NFV also mediated a dose-dependent increase in endoplasmic reticulum stress-related molecules associated with long-term inhibition of protein synthesis and concurrent cell death; such events were accompanied by a proapoptotic environment, signaled by increased phospho-eIF2α, ATF4, and CHOP, increased Bax/Bcl-2 ratio, and cleaved executer caspase-7. Finally, we show that NFV potentiates the short-term cell cycle arrest and long-term toxicity caused by the proteasome inhibitor bortezomib. Overall, our in vitro study demonstrates that NFV can therapeutically target HGSOC cells of differential platinum sensitivities via several mechanisms, suggesting its prospective repurposing benefit considering its good safety profile.