Recent studies have shown that itraconazole can induce autophagy thereby inhibiting glioblastoma growth via downregulation of steroid carrier protein 2 expression and redistribution of intracellular cholesterol 7. It is widely used for the prevention and treatment of systemic fungal infections 5, 6. Itraconazole is an antifungal drug of the triazole class, with a high bioavailability, broad spectrum and few side effects. However, various complications of surgical resection and adverse effects of radiotherapy and chemotherapy, as well as resistance to drugs, have affected the efficacy and adherence to treatment 4. At present, colon cancer is mainly treated by surgical intervention combined with radio and chemotherapies, according to the guidelines of the National Comprehensive Cancer Network (NCCN) 3. It is the second most common cancer in women (9.2%) and the third most common in men (10%) 2. Thus, itraconazole may be a potential and effective therapy for the treatment of colon cancer.Ĭolorectal cancer is a common tumor of the gastrointestinal tract ranking fourth and fifth in developed and developing countries respectively 1. Moreover, treatment with itraconazole produced significant cancer inhibition in HCT-116-bearing mice. After using the Hedgehog agonist recombinant human Sonic Hedgehog (rhshh), itraconazole could counteract the activation of rhshh. In addition, the Hedgehog pathway was found to be involved in activation of itraconazole-mediated autophagy.
Itraconazole treatment inhibited cell proliferation via G1 cell cycle arrest as well as autophagy-mediated apoptosis of SW-480 and HCT-116 colon cancer cells. Colon cancer cell xenograft mouse models were also established. The images of autophagy flux and formation of autophagosomes were observed by laser scanning confocal and/or transmission electron microscopy. Autophagy and signal proteins were detected by western blotting and cell proliferation-associated antigen Ki-67 was measured using immunohistochemistry. Cell apoptosis and cell cycle distribution of the colon cancer cell lines SW-480 and HCT-116 were detected by flow cytometry and terminal TUNEL assay. In the present study, we investigated whether itraconazole induces autophagy-mediated cell death of colon cancer cells through the Hedgehog signaling pathway. Recently, it has been reported to be effective in suppressing tumor growth by inhibiting the Hedgehog signaling pathway and angiogenesis. Itraconazole is as an antifungal medication used to treat systemic fungal infections.
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