Itraconazole exerts its anti-melanoma effect by suppressing Hedgehog, Wnt, and PI3K/mTOR signaling pathways

Abstract

Malignant melanoma is the deadliest form of all skin cancers. Itraconazole, a commonly used systemic antifungal drug, has been tested for its anti-tumor effects on basal cell carcinoma, prostate cancer, and non-small cell lung cancer. Whether itraconazole has any specific anti-tumor effect on melanoma remains unknown. However, the goal of this study is to investigate the effect of itraconazole on melanoma and to reveal some details of its underlying mechanism. In the in vivo xenograft mouse model, we find that itraconazole can inhibit melanoma growth and extend the survival of melanoma xenograft mice, compared to non-itraconazole-treated mice. Also, itraconazole can significantly inhibit cell proliferation, as demonstrated by Ki-67 staining in itraconazole-treated tumor tissues. In in vitro, we show that itraconazole inhibits the proliferation and colony formation of both SK-MEL-28 and A375 human melanoma cells. Moreover, we demonstrate that itraconazole significantly down-regulates Gli-1, Gli-2, Wnt3A, β-catenin and cyclin D1, while it up-regulates Gli-3 and Axin-1, indicating potent inhibitory effects of itraconazole on Hedgehog (Hh) and Wnt signaling pathways. Furthermore, itraconazole significantly suppresses the PI3K/mTOR signaling pathway – indicated by the down-regulated phosphorylation of p70S6K, 4E-BP1 and AKT – but has no effect on the phosphorylation of MEK or ERK. Our data suggest that itraconazole inhibits melanoma growth through an interacting regulatory network that includes Hh, Wnt, and PI3K/mTOR signaling pathways. These results suggest that this agent has several potent anti-melanoma features and may be useful in the synergesis of other anti-cancer drugs via blockage of the Hh, Wnt and PI3K/mTOR signaling pathways.

Repurposing itraconazole as an anticancer agent

“…Itraconazole inhibits AKT (protein kinase B)/mechanistic target of rapamycin (mTOR) signaling in human umbilical vein endothelial cells (HUVECs), glioblastoma, endometrial carcinoma (EC) and melanoma cells (10)(11)(12)(13)(14). Inhibition of Hedgehog signaling was observed in basal cell carcinoma, medulloblastoma, pleural mesothelioma, breast cancer and melanoma cells (9,(14)(15)(16)(17), but not in EC cells (13).…”

“…Inhibition of Hedgehog signaling was observed in basal cell carcinoma, medulloblastoma, pleural mesothelioma, breast cancer and melanoma cells (9,(14)(15)(16)(17), but not in EC cells (13). Inhibition of Wnt/β-catenin signaling was observed in basal cell and examined in melanoma cells (14). Itraconazole also induced autophagic cell death in medulloblastoma cells as well as in breast cancer cells (12,17), and suppressed lymphangiogenesis in lung carcinoma cells (18).…”

Itraconazole inhibits invasion and migration of pancreatic cancer cells by suppressing TGF-β/SMAD2/3 signaling

“…A recent report also revealed that ITZ-mediated hedgehog pathway inhibition inhibited proliferation as well as induced apoptosis and autophagic cell death in breast cancer, thus inhibiting tumor growth in vivo (37). Besides the hedgehog pathway, a recent study reported that ITZ exerts its anticancer effect by impairing a regulatory network involving the hedgehog, Wnt, and PI3K/mTOR signaling pathways, thus inhibiting the growth of melanoma and extending the survival of mice harboring melanoma xenografts (38). here, we found that treatment with ITZ may interfere with TGF-β/SMAD2/3 signaling.…”

Repurposing the serotonin agonist Tegaserod as an anticancer agent in melanoma: molecular mechanisms and clinical implications

“…1a). Positive hits included members of the statin, antifungal and antihelmintics categories, most of which are already being pre-clinically evaluated as therapeutics in melanoma or other cancers [12][13][14]. Others, belonging to the microtubule disruptors, antimetabolite and topoisomerase inhibitors are already in use as anticancer agents [15].…”