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

Guanzhao Liang,Qiong Wang,Weida Liu,Huan Mei,Dongmei Li,Yongnian Shen,Musang Liu

doi:10.18632/oncotarget.15324

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.

Highlights

Malignant melanoma is one of the most aggressive cancers, accounting for roughly 4% of human skin cancers but producing approximately 80% of deaths due to cutaneous neoplasms [1]
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 phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathways
We find that itraconazole increases Gli-3, Axin-1 expression but decreases Gli-1, Gli-2, Axin-1, β-catenin, Wnt3A and Cyclin D1 expression in both melanoma cell lines when compared with untreated cells

Summary

Introduction

Malignant melanoma is one of the most aggressive cancers, accounting for roughly 4% of human skin cancers but producing approximately 80% of deaths due to cutaneous neoplasms [1]. The outcome of patients with metastatic melanoma remains very poor, with a 5-year survival rate of only 5%–15%, a rate which has not seen any significant improvement despite intensive therapeutic efforts over many decades [2]. 50-70% and 15%-30% of melanoma patients, respectively [3]. Some genetic alterations on signaling molecules such as CDKN2A, PDK1, PTEN, and AKT have been associated with the pathogenesis of melanoma [4]. Other recent studies have confirmed that Hh and Wnt signal transduction pathways are relevant to the formation and progression of melanoma [6, 7]. Efforts to focus on development of www.impactjournals.com/oncotarget inhibitors targeting these pathways are critically important for cancer treatment, and in particular melanoma

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