Itraconazole Revival: Unlocking Its Anticancer Potential

Abstract

Itraconazole is an antifungal drug that is a member of the triazole class of medications. It works by preventing the manufacture of ergosterol, which is an essential part of fungal cell membranes, which interferes with the structure and function of the membranes. However, more research is required to fully establish its efficacy and the best treatment regimens for various cancer types. Itraconazole may have anti-cancer properties, especially against cancers like non-small cell lung cancer, prostate cancer, and basal cell carcinoma. Studies have shown potential benefits in inhibiting tumor growth and progression by targeting the Hedgehog signaling pathway.

Introduction

Itraconazole, originally developed as a broad-spectrum antifungal agent in the 1980s, has demonstrated significant anticancer potential across various tumor types due to its multiple mechanisms of action. These include:

• Inhibition of key signaling pathways like Hedgehog (Hh), PI3K/AKT/mTOR, and Wnt/β-catenin

• Angiogenesis and lymphangiogenesis suppression

• Cell cycle arrest, apoptosis induction, and autophagy activation

• Overcoming drug resistance, especially through inhibition of P-glycoprotein (ABCB1)

Itraconazole has shown efficacy in multiple cancers, including:

• Lung, esophageal, gastric, colon, breast, prostate, ovarian, melanoma, pancreatic, liver, and lymphoma

• It also impacts cancer stem cells (CSCs) and modulates the tumor microenvironment, suggesting potential for reducing recurrence and metastasis.

Various formulations and delivery strategies (e.g., nanoparticles, lipid nanocarriers, chitosan coatings) have been developed to improve its bioavailability, tumor targeting, and reduce systemic toxicity.

Challenges:

• The major drawback of using itraconazole in cancer treatment is its strong inhibition of CYP3A4, a key liver enzyme involved in metabolizing many anticancer drugs, leading to potential drug-drug interactions.

• It may also impair immune responses and interfere with immunotherapy (e.g., with rituximab).

• There is a lack of large-scale, randomized clinical trials, limiting broader adoption in oncology.

Future Directions:

• Development of itraconazole analogs that retain anticancer activity but avoid CYP3A4 inhibition.

• Focus on targeting CSCs and the tumor microenvironment to prevent relapse and resistance.

• More clinical trials are needed to confirm efficacy and identify biomarkers for patient stratification.

• Databases like ClinicalTrials.gov list ongoing studies exploring itraconazole’s use in oncology.

Conclusion

Nowadays, repurposing medications is rapidly gaining popularity in the medical industry. Compared to creating new treatments, the technique saves time and money. This is the situation with itraconazole. Itraconazole was first used to treat fungal infections. However, a medical finding more than ten years ago demonstrated that itraconazole is highly effective in treating a variety of cancers, including skin, prostate, and lung cancers. As a result, its prompt repurposing gave the medication fresh life. By blocking cellular growth pathways and preventing the development of new blood vessels, itraconazole treats cancer. Through direct action on the SMO protein, it suppresses the Hedgehog pathway. One essential transmembrane protein in the Hedgehog (HH) signaling pathway is Smoothened (SMO). A highly conserved signaling pathway, the Hedgehog-GLI (HH-GLI) pathway is essential for regulating tissue patterning and cell-to-cell contact. Cancer and birth abnormalities are caused by mutations in proteins that transmit HH signals between cells. The various anti-cancer properties of itraconazole have been explained by a number of different modes of action. These consist of: suppression of the hedgehog pathway, Induction of autophagy, Multidrug resistance reversal and Anti-angiogenesis.

References

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Copyright

Copyright © 2025 Adnan Raza, Parun Mahor, Anjali Gangwar, Mohd. Adil Tahseen, Mohd Shoaib. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.