Drug repurposing has emerged as an increasingly important strategy in oncology, offering a faster and more cost-effective route to new therapies by leveraging medications with established safety profiles. One compelling example is itraconazole, a broad-spectrum antifungal drug that has been used clinically for decades. A comprehensive 2017 review article titled “Repurposing itraconazole for the treatment of cancer” by Rachel Pounds, Sarah Leonard, Christopher Dawson, and Sean Kehoe, published in Oncology Letters, summarizes a growing body of preclinical and clinical evidence demonstrating that itraconazole also possesses significant antineoplastic activity across multiple cancer types.

Unlike conventional chemotherapeutic agents that primarily target rapidly dividing cells, itraconazole exerts its anticancer effects through multiple biological pathways central to tumor growth and survival. One of its most notable mechanisms is inhibition of the Hedgehog (Hh) signaling pathway, a developmental pathway that is aberrantly reactivated in many cancers. The review highlights that itraconazole suppresses Hedgehog signaling by acting on the Smoothened (SMO) protein, a key pathway regulator. Importantly, itraconazole binds to a site on SMO that is distinct from those targeted by other Hedgehog inhibitors, which may explain its effectiveness in tumors that have developed resistance to standard SMO-targeting drugs. This unique mechanism also provides a rationale for combining itraconazole with other anticancer agents to enhance therapeutic efficacy.

In addition to Hedgehog pathway inhibition, itraconazole demonstrates strong anti-angiogenic properties. Tumor growth beyond a minimal size depends on angiogenesis, the formation of new blood vessels that supply oxygen and nutrients. The review describes evidence showing that itraconazole inhibits vascular endothelial growth factor (VEGF) signaling, suppresses endothelial cell proliferation, and reduces endothelial migration and tube formation. By disrupting these key steps in blood vessel formation, itraconazole effectively starves tumors of their vascular support, limiting growth and metastatic potential. This anti-angiogenic activity distinguishes itraconazole from many antifungal drugs and places it in a category with targeted anti-vascular cancer therapies.

The review further reports that itraconazole interferes with additional cancer-related processes, including cell cycle progression and autophagy. By slowing or arresting the cell cycle, itraconazole reduces cancer cell proliferation, while modulation of autophagy can either promote cancer cell death directly or sensitize tumors to other treatments. These multifaceted effects are particularly valuable in oncology, where redundancy and adaptability in cancer signaling networks often undermine single-target therapies. The ability of itraconazole to act on several pathways simultaneously may help overcome drug resistance, a major obstacle in cancer treatment.

Clinical evidence summarized in the review supports the translational relevance of these mechanisms. Itraconazole has shown promising activity in a variety of malignancies, including basal cell carcinoma, non-small cell lung cancer, prostate cancer, ovarian cancer, breast cancer, and pancreatic cancer. In several studies, itraconazole was used in combination with standard cytotoxic chemotherapy or targeted agents, resulting in improved response rates, delayed disease progression, or extended survival compared with conventional treatment alone. While many of these studies were early-phase or exploratory, their consistency across different tumor types strengthens the argument for itraconazole’s broad anticancer potential.

A major advantage emphasized by the authors is itraconazole’s existing regulatory approval and well-characterized safety profile. As a U.S. Food and Drug Administration–approved antifungal medication, itraconazole is relatively inexpensive and widely available, lowering barriers to clinical testing and eventual implementation if efficacy is confirmed. This contrasts sharply with the high cost and long development timelines associated with novel oncology drugs. The review therefore positions itraconazole as an attractive candidate for further clinical investigation, particularly in combination regimens designed to enhance treatment response or overcome resistance.

In conclusion, the 2017 review published in Oncology Letters provides compelling evidence that itraconazole is far more than an antifungal agent (Oncology Letters, 2017; doi: 10.3892/ol.2017.6569). By inhibiting Hedgehog signaling, suppressing angiogenesis, interfering with cell cycle progression, and modulating autophagy, itraconazole targets multiple hallmarks of cancer. Although additional large-scale clinical trials are needed to establish its definitive role in oncology, the existing data strongly support itraconazole as a promising, safe, and cost-effective candidate for drug repurposing in cancer therapy.