HIV‐protease inhibitors for the treatment of cancer: Repositioning HIV protease inhibitors while developing more potent NO‐hybridized derivatives?

Abstract

The possible use of HIV protease inhibitors (HIV-PI) as new therapeutic option for the treatment of cancer primarily originated from their success in treating HIV-related Kaposi's sarcoma (KS). While these findings were initially attributed to immune reconstitution and better control of oncogenic viral infections, the number of reports on solid tumors, KS, lymphoma, fibrosarcoma, multiple myeloma and prostate cancer suggest other mechanisms for the anti-neoplastic activity of PIs. However, a major drawback for the possible adoption of HIV-PIs in the therapy of cancer relies on their relatively weak anticancer potency and important side effects. This has propelled several groups to generate derivatives of HIV-PIs for anticancer use, through modifications such as attachment of different moieties, ligands and transporters, including saquinavir-loaded folic acid conjugated nanoparticles and nitric oxide (NO) derivatives of HIV-PIs. In this article, we discuss the current preclinical and clinical evidences for the potential use of HIV-PIs, and of novel derivatives, such as saquinavir-NO in the treatment of cancer.

HIV‐1, HAART and cancer: A complex relationship

“…PIs induce cell growth arrest, endoplasmic reticulum stress, caspase‐dependent apoptosis, autophagy (for review see). Moreover, PIs are known for their antiangiogenic and radiosensitizing effects . PIs action is associated with inhibition of phosphatidylinositol 3‐kinase (PI3K)/Akt pathway; one of the possible mechanisms is binding to Hsp90 and inhibiting its chaperone function followed by decreased PI3K/Akt signaling .…”

“…Detailed docking analysis has shown that PIs can be potent Hsp90 inhibitors; their binding capacity to Hsp90 decreases in the following order: Nelfinavir, Indinavir, Saquinavir, Ritonavir, Lopinavir, Tipranavir, Darunavir and Amprenavir§ . Indeed, among all PIs, nelfinavir seems to have the highest anticancer activity . It is noteworthy that a longitudinal study of antitumor effects of PIs and especially, nelfinavir, is nuanced by the fact that in 2007 Roche's Viracept (nelfinavir mesylate) was discovered to be contaminated by a mutagenic compound .…”

“…They have been reported to inhibit the growth of various cancer cell lines in vitro as well as tumors in in vivo xenografts models. [136][137][138][139] PIs induce cell growth arrest, endoplasmic reticulum stress, caspase-dependent apoptosis, autophagy (for review see [140][141][142] ). Moreover, PIs are known for their antiangiogenic and radiosensitizing effects.…”

“…Moreover, PIs are known for their antiangiogenic and radiosensitizing effects. 141,143 PIs action is associated with inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt pathway; one of the possible mechanisms is binding to Hsp90 and inhibiting its chaperone function followed by decreased PI3K/Akt signaling. 137,138 Together and independently of each other, PI3K and its downstream kinase Akt regulate various cell processes such as growth, proliferation, survival, migration, apoptosis and their hyperactivation is a cancer hallmark.…”

The HIV protease inhibitor, nelfinavir, as a novel therapeutic approach for the treatment of refractory pediatric leukemia

“…Finally, a phase I a clinical trial of NFV against various adult solid tumors also showed partial responses in up to 3 of 11 of evaluable patients with drug safety and tolerability 15. Additionally, there is some preclinical work on PI-derivatives showing promising results, including in leukemia 19–22…”