Itraconazole suppresses the growth of glioblastoma through induction of autophagy

Li, Rui; Li, Jingyi; Zhang, Tao; Zou, Linzhi; Chen, Yi; Wang, Kui; Y, Lei; Yuan, Kefei; Li, Yi; Jiang, Lan; Cheng, Lin; Xie, Na; Xiang, Rong; Nice, Edouard C.; Huang, Canhua; Wei, Yuquan

doi:10.4161/auto.28912

Cited by 164 publications

(137 citation statements)

References 75 publications

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“…In HUVECs, itraconazole inhibited intracellular cholesterol trafficking to the plasma membrane by binding to Niemann-Pick C1 protein, resulting in cholesterol depletion (26). In glioblastoma cells, the redistribution of cholesterol was induced by the downregulation of sterol carrier protein (SCP2) (12), which is located in numerous organelles including mitochondria (27). In EC cells, the transcription of SCP2 was observed to be unaffected by itraconazole treatment.…”

Section: Repurposing Itraconazole As An Anticancer Agent (Review)mentioning

confidence: 98%

“…Itraconazole inhibits AKT (protein kinase B)/mechanistic target of rapamycin (mTOR) signaling in human umbilical vein endothelial cells (HUVECs), glioblastoma, endometrial carcinoma (EC) and melanoma cells (10)(11)(12)(13)(14). Inhibition of Hedgehog signaling was observed in basal cell carcinoma, medulloblastoma, pleural mesothelioma, breast cancer and melanoma cells (9,(14)(15)(16)(17), but not in EC cells (13).…”

Section: Preclinical Datamentioning

confidence: 99%

“…Inhibition of Wnt/β-catenin signaling was observed in basal cell and examined in melanoma cells (14). Itraconazole also induced autophagic cell death in medulloblastoma cells as well as in breast cancer cells (12,17), and suppressed lymphangiogenesis in lung carcinoma cells (18).…”

Section: Preclinical Datamentioning

confidence: 99%

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Repurposing itraconazole as an anticancer agent

et al. 2017

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Abstract. Itraconazole, a common anti-fungal agent, has demonstrated potential anticancer activity, including reversing chemoresistance mediated by P-glycoprotein, modulating the signal transduction pathways of Hedgehog, mechanistic target of rapamycin and Wnt/β-catenin in cancer cells, inhibiting angiogenesis and lymphangiogenesis, and possibly interfering with cancer-stromal cell interactions. Clinical trials have suggested the clinical benefits of itraconazole monotherapy for prostate cancer and basal cell carcinoma, as well as the survival advantage of combination chemotherapy for relapsed non-small cell lung, ovarian, triple negative breast, pancreatic and biliary tract cancer. As drug repurposing is cost-effective and timesaving, a review was conducted of preclinical and clinical data focusing on the anticancer activity of itraconazole, and discusses the future directions for repurposing itraconazole as an anticancer agent.

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Section: Repurposing Itraconazole As An Anticancer Agent (Review)mentioning

confidence: 98%

Section: Preclinical Datamentioning

confidence: 99%

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Repurposing itraconazole as an anticancer agent

et al. 2017

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“…In the scenario of tumor development, autophagy eliminates the source of cellular damage and protects the cells from stress induced by chemotherapy or radiation, which represents a fine mechanism of negative feedback regulation. However, in the recent decade, it has become apparent that the consequence of autophagy varies significantly under different circumstances (5,6). To date, cytoprotective, cytostatic, cytotoxic, and nonprotective autophagy have been proposed as the four main functional forms of autophagy in the context of anticancer therapy (7).…”

Section: Introductionmentioning

confidence: 99%

Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer

et al. 2016

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Breast cancer is the most common cancer among women worldwide, yet successful treatment remains a clinical challenge. Ivermectin, a broad-spectrum antiparasitic drug, has recently been characterized as a potential anticancer agent due to observed antitumor effects. However, the molecular mechanisms involved remain poorly understood. Here, we report a role for ivermectin in breast cancer suppression by activating cytostatic autophagy both in vitro and in vivo. Mechanistically, ivermectin-induced autophagy in breast cancer cells is associated with decreased P21-activated kinase 1 (PAK1) expression via the ubiquitinationmediated degradation pathway. The inhibition of PAK1 decreases the phosphorylation level of Akt, resulting in the blockade of the Akt/mTOR signaling pathway. In breast cancer xenografts, the ivermectin-induced cytostatic autophagy leads to suppression of tumor growth. Together, our results provide a molecular basis for the use of ivermectin to inhibit the proliferation of breast cancer cells and indicate that ivermectin is a potential option for the treatment of breast cancer. Cancer Res; 76(15); 4457-69. Ó2016 AACR.

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“…Moreover, ITCZ is the only azole anti-fungal that is known to have potent anti-angiogenic and anti-proliferative activities in non-small cell lung cancer and glioblastoma cells (10,11), and has been shown to prolong the overall survival of patients with metastatic pancreatic cancer, ovarian cancer and breast cancer (12)(13)(14)(15). Sano et al (16) reported that ITCZ was capable of reducing the inflammatory degree, mucosal hyperplasia and Candida infection in alloxan-induced diabetic rats (16), while Verspeelt et al (17) reported that ITCZ was safe and efficient against dermatological disorders in diabetic patients.…”

Section: Introductionmentioning

confidence: 99%

Itraconazole attenuates hepatic gluconeogenesis and promotes glucose uptake by regulating AMPK pathway

Liu

et al. 2017

Exp Ther Med

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Abstract. The primarily metabolic abnormality in type 2 diabetes mellitus (T2DM) is the defect in gluconeogenesis and glucose uptake. Itraconazole (ITCZ) is a traditional azole drug with anti-fungal and anticancer properties. However, limited attention has been directed towards the contribution of ITCZ to hepatic gluconeogenesis and glucose uptake in T2DM. The present study aimed to investigate the potential effects of ITCZ on hepatic gluconeogenesis and glucose uptake as well as the underlying mechanisms. No obvious change in cell viability was detected by MTT assay in HepG2 cells with ITCZ treatment at gradually increasing concentrations. Western blot analysis demonstrated that the phosphorylation level of 5' adenosine monophosphate-activated protein kinase (AMPK) was significantly elevated by ITCZ treatment at ≥5 µg/ml (P<0.05). Moreover, ITCZ repressed the gluconeogenesis of HepG2 cells, as evidenced by the dose-dependently increased glycogen synthase kinase 3β phosphorylation level and a notably decreased glucose production rate (P<0.05). Simultaneously, the expression of peroxisome proliferator-activated receptor γ co-activator 1α, phosphoenolpyr uvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in HepG2 cells was reduced by ITCZ in a dose-dependent manner (P<0.001). Furthermore, a 2-deoxyglucose uptake assay revealed that the glucose uptake of HepG2 cells was notably enhanced, accompanied by the ITCZ dose-dependent upregulation of glucose transporter-4 (GLUT-4) (P<0.05). Conversely, silencing of AMPK by small interfering RNA resulted in an increase of ITCZ-reduced gluconeogenesis and inhibition of ITCZ-induced glucose uptake with relative upregulation of PEPCK and G6Pase and downregulation of GLUT4 in the presence of 50 µg/ml ITCZ (P<0.05). Overall, the results indicated that AMPK has an important role in regulating ITCZ-induced glucose uptake by stimulating GLUT4 in HepG2 cells. Therefore, ITCZ may become a promising candidate for T2DM therapy.

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Itraconazole suppresses the growth of glioblastoma through induction of autophagy

Cited by 164 publications

References 75 publications

Repurposing itraconazole as an anticancer agent

Repurposing itraconazole as an anticancer agent

Ivermectin Induces Cytostatic Autophagy by Blocking the PAK1/Akt Axis in Breast Cancer

Itraconazole attenuates hepatic gluconeogenesis and promotes glucose uptake by regulating AMPK pathway

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