Metformin Inhibits Growth of Human Glioblastoma Cells and Enhances Therapeutic Response

Sesen, Julie; Dahan, Perrine; Scotland, Sarah; Saland, Estelle; Dang, V.; Lemarié, Anthony; Tyler, Betty; Brem, Henry; Toulas, Christine; Moyal, Elizabeth Cohen Jonathan; Sarry, Jean Emmanuel; Skuli, Nicolas

doi:10.1371/journal.pone.0123721

Cited by 163 publications

(181 citation statements)

References 58 publications

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“…In contrast, temozolomideinduced cell death did not implicate caspase-3 activation, suggesting the involvement of other modes of cell death, such as autophagy [72]. Autophagy is usually reduced in cells with a large number of lipid droplets, which could partly explain the limited effectiveness of temozolomide against glioblastoma tumors [73,74].…”

Section: Discussionmentioning

confidence: 95%

Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma

Zhang

Cui

Amiri

et al. 2016

European Journal of Pharmaceutics and Biopharmaceutics

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a b s t r a c tIncreased lipid droplet number and fatty acid synthesis allow glioblastoma multiforme, the most common and aggressive type of brain cancer, to withstand accelerated metabolic rates and resist therapeutic treatments. Lipid droplets are postulated to sequester hydrophobic therapeutic agents, thereby reducing drug effectiveness. We hypothesized that the inhibition of lipid droplet accumulation in glioblastoma cells using pyrrolidine-2, a cytoplasmic phospholipase A2 alpha inhibitor, can sensitize cancer cells to the killing effect of curcumin, a promising anticancer agent isolated from the turmeric spice. We observed that curcumin localized in the lipid droplets of human U251N glioblastoma cells. Reduction of lipid droplet number using pyrrolidine-2 drastically enhanced the therapeutic effect of curcumin in both 2D and 3D glioblastoma cell models. The mode of cell death involved was found to be mediated by caspase-3. Comparatively, the current clinical chemotherapeutic standard, temozolomide, was significantly less effective in inducing glioblastoma cell death. Together, our results suggest that the inhibition of lipid droplet accumulation is an effective way to enhance the chemotherapeutic effect of curcumin against glioblastoma multiforme.

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Section: Discussionmentioning

confidence: 95%

Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma

Zhang

Cui

Amiri

et al. 2016

European Journal of Pharmaceutics and Biopharmaceutics

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“…Metformin reduced proliferation in hPASMCs consistent with the antiproliferative effects of metformin reported in other cell types, (MCF7s and glioma cells in cancers). 32,33 We considered possible mechanisms by which metformin could be exerting its therapeutic and antiproliferative effects.…”

Section: Discussionmentioning

confidence: 99%

Metformin Reverses Development of Pulmonary Hypertension via Aromatase Inhibition

et al. 2016

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H uman pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature, which often leads to right heart failure. PAH is characterized by elevated pulmonary pressure (>25 mm Hg at rest), vascular remodeling, and occlusive pulmonary vascular lesions. Although survival rates are improving slowly; there remains an unacceptably poor survival rate. 1 Females are more susceptible to PAH than males, as indicated in, for example, the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) registry where ≈80% of the patients registered were female.2,3 However, male patients have a poorer survival rate than females, implicating sex hormones in both PAH susceptibility and survival. 4 Consequently, the role of estrogens in PAH has been accumulating significant interest. [5][6][7][8] There is an estrogen paradox however as while exogenous estrogen may be protective against experimental pulmonary hypertension (PH) and right ventricular (RV) hypertrophy in rodent models, [9][10][11][12] endogenous estrogen is causative in female animal models. [13][14][15][16][17] Estrogen is synthesized from testosterone through the enzyme aromatase and inhibition of aromatase attenuates experimental PH but only in females. 17 Estrogen can be metabolized through the cytochrome p450 1B1 (CYP1B1) enzyme to form the mitogenic 16α-hydroxyestrone, a metabolite established to be pathogenic in PH. 16 Furthermore, single-nucleotide polymorphisms of CYP1B1 have been recently identified to be associated with PH and indicated to play a key role in sexual dimorphism in RV failure. 18 One transcription factor for CYP1B1 is the aryl hydrocarbon receptor (AhR), suppression of which has been shown to be antiproliferative (protective) in PH. 19 Metformin is a well-established drug for use in type 2 diabetes mellitus 20,21 and has been demonstrated to activate AMP-activated protein kinase (AMPK) in many tissues, although AMPK does not underlie the hypoglycemic actions of metformin. 22 AMPK is a ubiquitously expressed serine/threonine protein kinase, which plays a critical role in cellular and organ metabolism. 23,24 In breast cancer and polycystic ovarian syndrome, the therapeutic effects of metformin involves the enhancement of the AMPK pathway and inhibition of the nuclear translocation of cyclic AMPresponsive element binding protein-regulated transcription coactivator 2 (CRTC2). CRTC2 (a downstream target of AMPK) can bind to the PII promoter site of the aromatase Abstract-Females are more susceptible to pulmonary arterial hypertension than males, although the reasons remain unclear. The hypoglycemic drug, metformin, is reported to have multiple actions, including the inhibition of aromatase and stimulation of AMP-activated protein kinase. Inhibition of aromatase using anastrazole is protective in experimental pulmonary hypertension but whether metformin attenuates pulmonary hypertension through this mechanism remains unknown. We investigated whether metformin affected aromatase activity and if it could r...

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“…Cellular Physiology and Biochemistry studies [18][19][20][21] have shown that metformin inhibited the proliferation of various types of tumour cells, including PC cells. In our study, we first found that metformin inhibited PSCs proliferation.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

OCT1-Mediated Metformin Uptake Regulates Pancreatic Stellate Cell Activity

Wu¹,

Qiu²,

Zhu³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Metformin treatment is reported to be associated with a lower incidence of and mortality from pancreatic cancer (PC) in type 2 diabetes patients. Activated pancreatic stellate cells (PSCs) are key stroma cells responsible for pancreatic fibrogenesis and PC progression. However, little research is about the influence of metformin on PSCs. Given the potential beneficial effects of metformin on PC, pancreatic tumour stroma is an important target for new therapeutics. We observed the effects of metformin on PSCs. We investigated the effects of metformin on human PSCs proliferation and the production of extracellular matrix (ECM) proteins. Methods: Cells were cultured with different concentrations of metformin (0-10 mmol/L). Cell proliferation was determined by immunofluorescence staining for nuclear Ki67 labelling. ECM production was studied by quantitative real-time polymerase chain reaction, immunoblotting and immunofluorescence microscopy. Adenosine monophosphate–activated protein kinase (AMPK), an important regulatory molecule responsible for metformin action, and the organic cation transporter member 1 (OCT1), which is believed to be the most important transporter for the pharmacological action of metformin, were investigated for their possible involvements in metformin-induced proliferation and ECM production. Results: Our results showed that metformin inhibited PSCs proliferation and decreased the production of ECM proteins by activation of AMPK phosphorylation. Silencing of OCT1 expression resulted in a reduction in the effects of metformin on PSCs activity. Conclusions: Collectively, the data indicate that OCT1 may contribute to uptake metformin and regulate PSCs activity. OCT1 is a target of metformin in regulating PSCs activity.

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Metformin Inhibits Growth of Human Glioblastoma Cells and Enhances Therapeutic Response

Cited by 163 publications

References 58 publications

Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma

Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma

Metformin Reverses Development of Pulmonary Hypertension via Aromatase Inhibition

OCT1-Mediated Metformin Uptake Regulates Pancreatic Stellate Cell Activity

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