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Autophagy. 2014 Jul;10(7):1241-55. doi: 10.4161/auto.28912. Epub 2014 May 15.

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

Author information

1
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital; Sichuan University; Chengdu, China; State Key Laboratory of Oral Diseases; West China Hospital of Stomatology; Sichuan University; Chengdu, China.
2
School of Biomedical Sciences; Chengdu Medical College; Chengdu, China.
3
College of Life Sciences; Sichuan University; Chengdu, China.
4
Department of Gastrointestinal Surgery; State Key Laboratory of Biotherapy; West China Hospital, Sichuan University, Chengdu, China.
5
State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital; Sichuan University; Chengdu, China.
6
Department of Biochemistry and Molecular Biology, Molecular Medicine and Cancer Research Center; Chongqing Medical University; Chongqing, China.
7
School of Medicine/Collaborative Innovation Center of Biotherapy; Nankai University; Tianjin, China.
8
Department of Biochemistry and Molecular Biology; Monash University; Clayton, Victoria Australia.

Abstract

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.

KEYWORDS:

BECN1-PtdIns3K complex; antiproliferative; autophagy; cholesterol trafficking; itraconazole

PMID:
24905460
PMCID:
PMC4203550
DOI:
10.4161/auto.28912
[Indexed for MEDLINE]
Free PMC Article

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