Metformin, an Old Drug, Brings a New Era to Cancer Therapy

He, Huan; Ke, Rong; Lin, Hui; Ying, Ying; Liu, Dan; Luo, Zhijun

doi:10.1097/ppo.0000000000000103

Cited by 48 publications

(45 citation statements)

References 52 publications

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“…Several drugs modulating the AMPK pathway also have been evaluated as potential antiangiogenic and anticancer agents. The widely prescribed, AMPK-activating antidiabetic drug metformin has been shown to inhibit angiogenesis in vitro and in vivo (55) and currently is being evaluated in several clinical trials for various types of cancer (56). However, the concentrations of metformin required to activate AMPK in HUVEC are at least 1,000 times higher than those required of itraconazole (in the range of low millimoles) (55), suggesting that itraconazole might be significantly more effective than metformin at inhibiting angiogenesis in patients.…”

Section: Discussionmentioning

confidence: 98%

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

Head

Shi

Zhao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

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Itraconazole, a clinically used antifungal drug, was found to possess potent antiangiogenic and anticancer activity that is unique among the azole antifungals. Previous mechanistic studies have shown that itraconazole inhibits the mechanistic target of rapamycin (mTOR) signaling pathway, which is known to be a critical regulator of endothelial cell function and angiogenesis. However, the molecular target of itraconazole that mediates this activity has remained unknown. Here we identify the major target of itraconazole in endothelial cells as the mitochondrial protein voltage-dependent anion channel 1 (VDAC1), which regulates mitochondrial metabolism by controlling the passage of ions and small metabolites through the outer mitochondrial membrane. VDAC1 knockdown profoundly inhibits mTOR activity and cell proliferation in human umbilical vein cells (HUVEC), uncovering a previously unknown connection between VDAC1 and mTOR. Inhibition of VDAC1 by itraconazole disrupts mitochondrial metabolism, leading to an increase in the cellular AMP:ATP ratio and activation of the AMP-activated protein kinase (AMPK), an upstream regulator of mTOR. VDAC1-knockout cells are resistant to AMPK activation and mTOR inhibition by itraconazole, demonstrating that VDAC1 is the mediator of this activity. In addition, another known VDAC-targeting compound, erastin, also activates AMPK and inhibits mTOR and proliferation in HUVEC. VDAC1 thus represents a novel upstream regulator of mTOR signaling in endothelial cells and a promising target for the development of angiogenesis inhibitors.

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Section: Discussionmentioning

confidence: 98%

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

Head

Shi

Zhao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

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“…Metformin, a clinically used antidiabetic drug, and phenformin, which had been in clinic use but was withdrawn because of toxicity, belong to the biguanides family; these agents activate AMPK by inhibiting mitochondrial respiratory chain and thus increasing intracellular AMP. Steady-state concentration of metformin in plasma of type 2 diabetes is in the range of 20-40 mM and can reach 50 mM in portal vein under oral administration at regularly prescribed doses (Owen et al, 2000); He et al, 2015). Metformin and phenformin are positively changed and require transporters to enter cells and mitochondria.…”

Section: Discussionmentioning

confidence: 99%

AMPK Inhibits the Stimulatory Effects of TGF-βon Smad2/3 Activity, Cell Migration, and Epithelial-to-Mesenchymal Transition

Lin¹,

Li²,

He³

et al. 2015

Mol Pharmacol

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AMP-activated protein kinase (AMPK), an important downstream effector of the tumor suppressor liver kinase 1 (LKB1) and pharmacologic target of metformin, is well known to exert a preventive and inhibitory effect on tumorigenesis; however, its role in cancer progression and metastasis has not been well characterized. The present study investigates the potential roles of AMPK in inhibiting cancer-cell migration and epithelialto-mesenchymal transition (EMT) by regulating the canonical transforming growth factor b (TGF-b) signaling pathway, an important promoting factor for cancer progression. Our results showed that activation of AMPK by metformin inhibited TGF-binduced Smad2/3 phosphorylation in cancer cells in a dosedependent manner. The effect of metformin is dependent on the presence of LKB1. A similar effect was obtained by expressing a constitutive active mutant of AMPKa1 subunit, whereas the expression of a dominant negative mutant of AMPKa1 or ablation of AMPKa subunits greatly enhanced TGF-b stimulation of Smad2/3 phosphorylation. As a consequence, expression of genes downstream of Smad2/3, including plasminogen activator inhibitor-1, fibronectin, and connective tissue growth factor, was suppressed by metformin in a LKB1-dependent fashion. In addition, metformin blocked TGF-b-induced inteleukin-6 expression through both LKB1-dependent and -independent mechanisms. Our results also indicate that activation of LKB1/AMPK inhibits TGF-b-stimulated cancer cell migration. Finally, TGF-b induction of EMT was inhibited by phenformin and enhanced by knockdown of LKB1 expression with shRNA. Together, our data suggest that AMPK could be a drug target for controlling cancer progression and metastasis.

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“…Metformin is the first-line oral therapy for Type 2 Diabetes (T2D) [1], and is also approved for use or used off-label in a variety of other diseases, such as polycystic ovary syndrome [2], gestational diabetes [3], pediatric obesity [4] and cancer [5,6]. Side effects of metformin are mainly gastrointestinal in 20% to 30% of patients, and in very rare cases include lactic acidosis [7].…”

Section: Introductionmentioning

confidence: 99%

Genomic Characterization of Metformin Hepatic Response

et al. 2016

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Metformin is used as a first-line therapy for type 2 diabetes (T2D) and prescribed for numerous other diseases. However, its mechanism of action in the liver has yet to be characterized in a systematic manner. To comprehensively identify genes and regulatory elements associated with metformin treatment, we carried out RNA-seq and ChIP-seq (H3K27ac, H3K27me3) on primary human hepatocytes from the same donor treated with vehicle control, metformin or metformin and compound C, an AMP-activated protein kinase (AMPK) inhibitor (allowing to identify AMPK-independent pathways). We identified thousands of metformin responsive AMPK-dependent and AMPK-independent differentially expressed genes and regulatory elements. We functionally validated several elements for metformin-induced promoter and enhancer activity. These include an enhancer in an ataxia telangiectasia mutated (ATM) intron that has SNPs in linkage disequilibrium with a metformin treatment response GWAS lead SNP (rs11212617) that showed increased enhancer activity for the associated haplotype. Expression quantitative trait locus (eQTL) liver analysis and CRISPR activation suggest that this enhancer could be regulating ATM, which has a known role in AMPK activation, and potentially also EXPH5 and DDX10, its neighboring genes. Using ChIP-seq and siRNA knockdown, we further show that activating transcription factor 3 (ATF3), our top metformin upregulated AMPK-dependent gene, could have an important role in gluconeogenesis repression. Our findings provide a genome-wide representation of metformin hepatic response, highlight important sequences that could be associated with interindividual variability in glycemic response to metformin and identify novel T2D treatment candidates.

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Metformin, an Old Drug, Brings a New Era to Cancer Therapy

Cited by 48 publications

References 52 publications

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

Antifungal drug itraconazole targets VDAC1 to modulate the AMPK/mTOR signaling axis in endothelial cells

AMPK Inhibits the Stimulatory Effects of TGF-βon Smad2/3 Activity, Cell Migration, and Epithelial-to-Mesenchymal Transition

Genomic Characterization of Metformin Hepatic Response

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