Repurposing the anti-parasitic agent pentamidine for cancer therapy; a novel approach with promising anti-tumor properties.

Pentamidine (PTM) is an aromatic diamidine administered for infectious diseases, e.g. sleeping sickness, malaria, and Pneumocystis jirovecii pneumonia. Due to similarities of cellular mechanisms between human cells and such infections, PTM has also been proposed for repurposing in non-infectious diseases such as cancer. Indeed, by modulating different signaling pathways such as PI3K/AKT, MAPK/ERK, p53, PD-1/PD-L1, etc., PTM has been shown to inhibit different properties of cancer, including proliferation, invasion, migration, hypoxia, and angiogenesis, while inducing anti-tumor immune responses and apoptosis. Given the promising implications of PTM for cancer treatment, however, the clinical translation of PTM in cancer is not without certain challenges. In fact, clinical trials have shown that systemic administration of PTM can be concurrent with serious adverse effects, e.g. hypoglycemia. Therefore, to reduce the administered doses of PTM, lower the risk of adverse effects, and prevent any potential drug resistance, while maintaining the anti-tumor efficacy, two main strategies have been suggested. One is combination therapy that employs PTM in conjunction with other anti-cancer modalities, such as chemotherapy and radiotherapy, and attacks tumor cells with significant additive or synergistic anti-tumor effects. The other is developing PTM-loaded nanocarrier drug delivery systems e.g. pegylated liposomes, chitosan-coated niosomes, squalene-based nanoparticles, hyaluronated lipid-polymer hybrid nanoparticles, etc., that offer enhanced pharmacokinetic characteristics, including increased bioavailability, sit-targeting, and controlled/sustained drug release. This review highlights the anti-tumor properties of PTM that favor its repurposing for cancer treatment, as well as, PTM-based combination therapies and nanocarrier delivery systems which can enhance therapeutic efficacy and simultaneously reduce toxicity.