Itraconazole is an orally active antifungal drug that can strongly inhibit the Hedgehog (Hh) signaling pathway, with an IC50 value is 800nM [1]. Itraconazole inhibits the NaV channel in the heart (IC50=4.2μM) and regulates the contractility of the left ventricle of the heart [2]. Itraconazole inhibits ergosterol synthesis by interacting with the substrate binding site of the fungal 14α-demethylase, increasing cell membrane permeability and disrupting cell membrane integrity[3]. Itraconazole has been widely used to inhibit the growth of various tumor cells and promote autophagy in cancer cells[4].
In vitro, Itraconazole treatment for 36 hours significantly inhibited the proliferation of human umbilical vein endothelial cells (HUVECs), with an IC50 value of 0.16µM[5]. Treatment of MCF-7 cells with 20µg/ml Itraconazole for 24 hours significantly induced cell death, accompanied by changes in mitochondrial membrane potential[6]. Treatment of SW-480 cells with 5µM Itraconazole for 48 hours significantly promoted cell apoptosis, induced G1 phase cell cycle arrest and significantly accumulated autophagosomes[7].
In vivo, Itraconazole treatment via intravenous administration at a dose of 20mg/kg/day for 4 days significantly reduced the fungal load in the lung tissues of mice with invasive pulmonary aspergillosis (IPA) and improved the survival rate of the mice[8]. Oral administration of 75mg/kg of Itraconazole twice daily for 2 weeks significantly inhibited tumor growth in a xenograft mouse model of MKN45 cells[9].
References:
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[2] Qu Y, Fang M, Gao B X, et al. Itraconazole decreases left ventricular contractility in isolated rabbit heart: mechanism of action[J]. Toxicology and applied pharmacology, 2013, 268(2): 113-122.
[3] De Beule K, Van Gestel J. Pharmacology of itraconazole[J]. Drugs, 2001, 61(Suppl 1): 27-37.
[4] Wei X, Liu W, Wang J Q, et al. “Hedgehog pathway”: a potential target of itraconazole in the treatment of cancer[J]. Journal of cancer research and clinical oncology, 2020, 146(2): 297-304.
[5] Chong C R, Xu J, Lu J, et al. Inhibition of angiogenesis by the antifungal drug itraconazole[J]. ACS chemical biology, 2007, 2(4): 263-270.
[6] Wang X, Wei S, Zhao Y, et al. Anti-proliferation of breast cancer cells with itraconazole: Hedgehog pathway inhibition induces apoptosis and autophagic cell death[J]. Cancer letters, 2017, 385: 128-136.
[7] Deng H, Huang L, Liao Z, et al. Itraconazole inhibits the Hedgehog signaling pathway thereby inducing autophagy-mediated apoptosis of colon cancer cells[J]. Cell Death & Disease, 2020, 11(7): 539.
[8] Tansho S, Abe S, Ono Y, et al. Efficacy of intravenous itraconazole against invasive pulmonary aspergillosis in neutropenic mice[J]. Journal of infection and chemotherapy, 2006, 12(6): 355-362.
[9] Hu Q, Hou Y C, Huang J, et al. Itraconazole induces apoptosis and cell cycle arrest via inhibiting Hedgehog signaling in gastric cancer cells[J]. Journal of Experimental & Clinical Cancer Research, 2017, 36(1): 50.