Itraconazole as a Promising Anti-Cancer Agent: Insights from Recent Studies

Itraconazole, a widely used antifungal medication, has emerged as a potential repurposed drug for cancer treatment. Beyond its antifungal properties, itraconazole has effectively inhibited cancer cell proliferation, migration, and survival through various molecular mechanisms. A growing body of research highlights its utility against several cancer types, including ovarian, colon, pancreatic, melanoma, and triple-negative breast cancer (TNBC). Below is a summary of findings from recent studies investigating the anti-cancer effects of itraconazole.

1. Itraconazole in Refractory Ovarian Cancer

A study explored the use of itraconazole in combination with chemotherapy in patients with refractory ovarian cancer. The study involved 55 patients divided into two groups: 19 received itraconazole with chemotherapy, while 36 received chemotherapy alone. Results showed that patients treated with itraconazole had significantly improved progression-free survival (PFS) of 103 days compared to 53 days in the control group, and overall survival (OS) was 642 days versus 139 days, respectively. Itraconazole likely exerts these effects by inhibiting P-glycoprotein, a protein associated with drug resistance, and reducing angiogenesis. These findings suggest that itraconazole could be a valuable adjunct therapy in the management of platinum-resistant ovarian cancer.

2. Itraconazole in Colon Cancer

A study involving 5,221 patients with colon cancer, based on the Taiwanese National Health Insurance Research Database, demonstrated that itraconazole improved the 5-year survival rate in patients with advanced-stage colon cancer (stages III and IV). In vitro experiments showed that itraconazole inhibited colon cancer cell proliferation, induced apoptosis, and caused cell cycle arrest at the G1 phase. Additionally, itraconazole triggered autophagic cell death and inhibited the transketolase (TKT) enzyme, a key player in cancer metabolism. These results underscore the potential of itraconazole as a repurposed therapy for colon cancer, particularly in combination with chemotherapy.

3. Itraconazole in Pancreatic Cancer

In a study focusing on pancreatic cancer, itraconazole was found to inhibit the invasion and migration of pancreatic cancer cells by suppressing the TGF-β/SMAD2/3 signaling pathway, a critical pathway involved in epithelial-to-mesenchymal transition (EMT) and metastasis. The drug also reversed EMT by increasing E-cadherin expression and decreasing N-cadherin and vimentin levels, markers associated with cancer cell migration. In vivo studies in a transgenic mouse model showed that itraconazole significantly reduced tumor growth and inhibited key markers of cancer progression. These findings suggest that itraconazole could be a valuable agent in limiting pancreatic cancer metastasis.

4. Itraconazole in Triple-Negative Breast Cancer (TNBC)

The combination of itraconazole and rapamycin was investigated as a treatment for triple-negative breast cancer (TNBC). The study found that the combination exerted synergistic effects, significantly inhibiting TNBC cell proliferation and migration. This combination led to cell cycle arrest at the G0/G1 phase and suppressed the AKT/mTOR signaling pathway, which is crucial for cancer cell survival. Although the combination did not induce significant apoptosis, its ability to halt cell cycle progression highlights the potential of itraconazole in treating TNBC when combined with other therapies.

5. Itraconazole in Melanoma

In a study targeting melanoma, itraconazole inhibited tumor growth by suppressing the Hedgehog (Hh), Wnt, and PI3K/mTOR signaling pathways. In vitro experiments revealed that itraconazole significantly reduced the proliferation of melanoma cells and colony formation, and it induced downregulation of key markers such as Gli-1, Gli-2, Wnt3A, and β-catenin. The drug also increased Gli-3 and Axin-1, which act as repressors of the Hh and Wnt pathways. In a mouse model, itraconazole reduced tumor volume, extended survival, and inhibited cell proliferation markers like Ki-67. These findings suggest that itraconazole could effectively treat melanoma by disrupting multiple oncogenic pathways.

The accumulating evidence on itraconazole's anti-cancer properties across various cancer types (including ovarian, colon, pancreatic, TNBC, and melanoma) demonstrates its potential as an effective repurposed drug. Its ability to inhibit essential cancer signaling pathways such as PI3K/mTOR, Hedgehog, and Wnt, along with its impact on cell cycle arrest, motility, apoptosis, and autophagy, makes itraconazole a promising candidate for combination therapies aimed at improving cancer treatment outcomes.

Combining azoles with other substances can enhance activity, reduce resistance, and lower toxicity. Various existing drugs, such as statins, bisphosphonates, and immunomodulators, show potential for enhancing azole treatments. Statins, for instance, can synergize with azoles. Many plant-based compounds, such as thymol, carvacrol, and berberine, demonstrate strong synergy with azoles, showing promise as adjuvants.

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Wu, Hua-Tao & Li, Chun-Lan & Fang, Ze-Xuan & Chen, Wen-Jia & Lin, Wen-Ting & Liu, Jing. (2022). Induced Cell Cycle Arrest in Triple-Negative Breast Cancer by Combined Treatment of Itraconazole and Rapamycin. Frontiers in Pharmacology. 13. 873131. 10.3389/fphar.2022.873131. 

Xu, Congcong & Zhuo, Yating & Liu, Yunyao & Chen, Hao. (2022). Itraconazole Inhibits the Growth of Cutaneous Squamous Cell Carcinoma by Targeting HMGCS1/ACSL4 Axis. Frontiers in Pharmacology. 13. 10.3389/fphar.2022.828983. 

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