Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro

Dykens, James A.; Jamieson, Joseph; Marroquin, Lisa D.; Nadanaciva, Sashi; Billis, Puja; Will, Yvonne

doi:10.1016/j.taap.2008.08.013

Cited by 196 publications

(189 citation statements)

References 32 publications

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“…This was possibly due to a buildup of lactate, a consequence of these cells relying on glycolysis to compensate for reduced ATP production via oxidative phosphorylation (Martinus et al 1993). The metformin toxicity profile seen in this study was comparable to those reported using primary human hepatocytes and HepG2 cells (Dykens et al 2008).…”

Section: Resultssupporting

confidence: 84%

Metformin induced expression of Hsp60 in human THP-1 monocyte cells

Tsuei

Martinus

2012

Cell Stress and Chaperones

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Metformin is in widespread clinical use for the treatment of diabetes mellitus in patients. It has been shown to inhibit mitochondrial bioenergetic functions by inhibiting complex I of the electron transport chain. The expression of mitochondrial-specific molecular stress protein Hsp60 is a key consequence of mitochondrial impairment. Since this protein has important immune-modulatory properties, we have investigated the expression of Hsp60 in human THP-1 monocyte cells exposed to metformin. In this study, we demonstrate significant up-regulation of Hsp60 at both mRNA and protein levels when these cells were exposed to metformin at therapeutic dosage levels. Interestingly, there was also an increase in expression of CD14 mRNA in these cells. This suggested a possible modulation of the differentiation rates of the THP-1 cells during exposure to metformin. As monocyte differentiation marks a critical step in atherosclerosis, these observations suggest that longterm exposure to metformin could have important implications for the diabetic patient.

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Section: Resultssupporting

confidence: 84%

Metformin induced expression of Hsp60 in human THP-1 monocyte cells

Tsuei

Martinus

2012

Cell Stress and Chaperones

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“…C Algire et al (Dykens et al, 2008), we observed decreased cellular ATP concentration with metformin exposure; however, we observed an important influence of LKB1 expression on this effect. Following 48-h exposure to 5 mM metformin, both MC38 and LLC1 cells showed a significant decrease in ATP of 40-50% under both low and high glucose conditions (Figure 7).…”

Section: Metformin Inhibits Tumor Growth Independent Of Lkb1contrasting

confidence: 45%

“…Metformin and other biguanides are mild inhibitors of complex I of the respiratory chain, and are known to reduce adenosine triphosphate (ATP) levels and increase the ratio of adenosine monophosphate to ATP in the cell (El Mir et al, 2000;Owen et al, 2000;Hardie, 2006;Dykens et al, 2008). The tumor suppressor LKB1 (Shackelford and Shaw, 2009) phosphorylates and activates adenosine monophosphate-activated protein kinase (AMPK) at Thr 172 when the ratio of intracellular adenosine monophosphate/ATP increases (Shaw et al, 2004;Jones et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo

et al. 2010

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Hypothesis-generating epidemiological research has suggested that cancer burden is reduced in diabetics treated with metformin and experimental work has raised questions regarding the role of direct adenosine monophosphate-activated protein kinase (AMPK)-mediated antineoplastic effects of metformin as compared with indirect effects attributable to reductions in circulating insulin levels in the host. We treated both tumor LKB1 expression and host diet as variables, and observed that metformin inhibited tumor growth and reduced insulin receptor activation in tumors of mice with diet-induced hyperinsulinemia, independent of tumor LKB1 expression. In the absence of hyperinsulinemia, metformin inhibited only the growth of tumors transfected with short hairpin RNA against LKB1, a finding attributable neither to an effect on host insulin level nor to activation of AMPK within the tumor. Further investigation in vitro showed that cells with reduced LKB1 expression are more sensitive to metformin-induced adenosine triphosphate depletion owing to impaired ability to activate LKB1-AMPK-dependent energy-conservation mechanisms. Thus, loss of function of LKB1 can accelerate proliferation in contexts where it functions as a tumor suppressor, but can also sensitize cells to metformin. These findings predict that any clinical utility of metformin or similar compounds in oncology will be restricted to subpopulations defined by host insulin levels and/or loss of function of LKB1.

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“…Wilcock and Bailey reported practically no metformin accumulation in skeletal muscle from normal mice, and no metformin accumulation at all in mice with streptozotocin-induced diabetes [16]. It has previously been suggested that metformin accumulates in the mitochondria [25], and therefore it cannot be completely ruled out that an accumulation of metformin can occur in human skeletal muscle mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Metformin-treated patients with type 2 diabetes have normal mitochondrial complex I respiration

et al. 2011

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Aims/hypothesis The glucose-lowering drug metformin has been shown to inhibit complex I of the mitochondrial electron transport chain in skeletal muscle. To investigate this effect in vivo we studied skeletal muscle mitochondrial respiratory capacity and content from patients with type 2 diabetes treated with metformin (n=14) or sulfonylurea (n= 8) and healthy control (n=18) participants. Methods Mitochondrial respiratory capacity was measured ex vivo in permeabilised muscle fibres obtained from the vastus lateralis muscle of all participants. The respiratory response to in vitro titration with metformin was measured in controls. Citrate synthase (CS) activity, and fasting plasma glucose, insulin and HbA 1c levels were measured and body composition was determined. Results Participants were matched for age, BMI and percentage body fat. Fasting plasma glucose concentrations were higher (p<0.05) in those treated with sulfonylureas and metformin than in controls. CS activity was comparable between metformin-treated and control participants, but tended to be lower in those receiving sulfonylureas. Mitochondrial respiratory capacity with substrates for complex I and complex I and II was comparable in the groups, both when estimated per mg of tissue and when normalised to CS activity. In vitro metformin titration demonstrated a dose-dependent inhibitory effect on complex I and II in human skeletal muscle at suprapharmacological concentrations. Conclusions/interpretation Metformin treatment does not inhibit mitochondrial complex I respiration in the electron transport chain in human skeletal muscle of patients with type 2 diabetes when measured ex vivo. Inhibition of complex I and II respiration in controls was demonstrated by metformin titration in vitro at doses well above those observed during metformin treatment.

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Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro

Cited by 196 publications

References 32 publications

Metformin induced expression of Hsp60 in human THP-1 monocyte cells

Metformin induced expression of Hsp60 in human THP-1 monocyte cells

Diet and tumor LKB1 expression interact to determine sensitivity to anti-neoplastic effects of metformin in vivo

Metformin-treated patients with type 2 diabetes have normal mitochondrial complex I respiration

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