HIV Protease Inhibitor Applications in Oncology

Human immunodeficiency virus (HIV) protease inhibitors were originally designed to block viral polyprotein processing but have demonstrated a remarkable capacity to interfere with key pathways in cancer cells. These agents exert antineoplastic effects by inducing endoplasmic reticulum stress, activating the unfolded protein response, inhibiting the proteasome and modulating survival kinases such as AKT. They promote apoptosis, cell‐cycle arrest and oxidative stress in a diverse range of tumour types, including colorectal, ovarian, breast, pancreatic and lung cancers. Preclinical investigations employing monolayer cultures, three‐dimensional spheroids and xenograft models have revealed the ability of these drugs to suppress proliferation, reduce metastatic potential and enhance sensitivity to established chemotherapeutics and radiotherapy. Oral bioavailability, a well‐characterised safety profile and global accessibility render HIV protease inhibitors attractive candidates for drug repurposing, particularly in resource‐limited settings. Early‐phase clinical trials have confirmed tolerability at doses exceeding those used in HIV management, with signs of antitumour activity in solid malignancies. The convergence of mechanistic insights—spanning cytochrome P450 targeting, endoplasmic reticulum perturbation and kinase pathway inhibition—underscores the multifaceted nature of these compounds and their prospective value as adjuncts or standalone agents in oncological practice.

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HIV Protease Inhibitor Applications in Oncology publication trend

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Technical terms

Endoplasmic reticulum stress: A cellular condition arising from accumulation of misfolded proteins in the endoplasmic reticulum, triggering adaptive signalling.

Unfolded protein response (UPR): A coordinated set of signalling pathways activated to restore proteostasis within the endoplasmic reticulum.

Proteasome: A multi‐subunit enzyme complex responsible for targeted degradation of intracellular proteins via the ubiquitin–proteasome system.

AKT signalling: A kinase‐driven pathway that regulates cell survival, growth and metabolism, often dysregulated in cancer.

Cytochrome P450 enzymes: A family of heme‐containing monooxygenases involved in the metabolism of xenobiotics and endogenous substrates.

Clonogenic survival assay: An in vitro method to assess the capacity of individual cells to form colonies, reflecting long-term reproductive viability.

References

1. Therapeutic Potential of Targeting the Cytochrome P450 Enzymes Using Lopinavir/Ritonavir in Colorectal Cancer: A Study in Monolayers, Spheroids and In Vivo Models. Cancers (2023).
2. Repurposing Alone and in Combination of the Antiviral Saquinavir with 5-Fluorouracil in Prostate and Lung Cancer Cells. International Journal of Molecular Sciences (2022).
3. Nelfinavir Induces Cytotoxicity towards High-Grade Serous Ovarian Cancer Cells, Involving Induction of the Unfolded Protein Response, Modulation of Protein Synthesis, DNA Damage, Lysosomal Impairment, and Potentiation of Toxicity Caused by Proteasome Inhibition. Cancers (2021).
4. A phase I trial of the HIV protease inhibitor nelfinavir in adults with solid tumors. Oncotarget (2014).