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Itraconazole suppresses the growth of glioblastoma through induction of autophagy: involvement of abnormal cholesterol trafficking.

Authors: Liu, R  Li, J  Zhang, T  Zou, L  Chen, Y  Wang, K  Lei, Y  Yuan, K  Li, Y  Lan, J  Cheng, L  Xie, N  Xiang, R  Nice, EC  Huang, C  Wei, Y 
Citation: Liu R, etal., Autophagy. 2014 Jul;10(7):1241-55. doi: 10.4161/auto.28912. Epub 2014 May 15.
Pubmed: (View Article at PubMed) PMID:24905460
DOI: Full-text: DOI:10.4161/auto.28912

Glioblastoma is one of the most aggressive human cancers with poor prognosis, and therefore a critical need exists for novel therapeutic strategies for management of glioblastoma patients. Itraconazole, a traditional antifungal drug, has been identified as a novel potential anticancer agent due to its inhibitory effects on cell proliferation and tumor angiogenesis; however, the molecular mechanisms involved are still unclear. Here, we show that itraconazole inhibits the proliferation of glioblastoma cells both in vitro and in vivo. Notably, we demonstrate that treatment with itraconazole induces autophagic progression in glioblastoma cells, while blockage of autophagy markedly reverses the antiproliferative activities of itraconazole, suggesting an antitumor effect of autophagy in response to itraconazole treatment. Functional studies revealed that itraconazole retarded the trafficking of cholesterol from late endosomes and lysosomes to the plasma membrane by reducing the levels of SCP2, resulting in repression of AKT1-MTOR signaling, induction of autophagy, and finally inhibition of cell proliferation. Together, our studies provide new insights into the molecular mechanisms regarding the antitumor activities of itraconazole, and may further assist both the pharmacological investigation and rational use of itraconazole in potential clinical applications.


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CRRD Object Information
CRRD ID: 11561946
Created: 2016-11-14
Species: All species
Last Modified: 2016-11-14
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.