Relevance of the OCT1 transporter to the antineoplastic effect of biguanides

Segal, Eric; Yasmeen, Amber; Beauchamp, Marie‐Claude; Rosenblatt, Joshua; Pollak, Michael; Gotlieb, Walter H.

doi:10.1016/j.bbrc.2011.09.134

Cited by 83 publications

(73 citation statements)

References 25 publications

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“…An important point to bear in mind is that effects of metformin are unlikely to be homogeneous across tissues, not only due to higher concentration in the portal circulation than the systemic circulation following oral dosing, but also due to the fact that tissues vary in their expression of the transport molecules required for metformin uptake. Although these transporters play a key role for metformin uptake at drug concentrations achievable in vivo , cellular accumulation of other more lipophilic biguanides, such as phenformin, are less dependent on active transport, and therefore may differ greatly from metformin in terms of tissue distribution and have greater antineoplastic activity, as suggested by laboratory studies (75)(76)(77).…”

Section: Effects At the Whole-organism Levelmentioning

confidence: 99%

“…Phenformin is associated with higher risk of lactic acidosis than metformin, but nevertheless has a better safety profi le than most antineoplastic agents in current use, and is more effective than metformin in preclinical models, probably because of its pharmacokinetic characteristics (75)(76)(77). There are libraries of many biguanides that could be screened for antineoplastic activity and/or used as lead compounds for optimization of pharmacokinetics.…”

Section: Identifying the Key Mechanisms Of Actionmentioning

confidence: 99%

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Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning

2012

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Laboratory research and pharmacoepidemiology are providing converging evidence that the widely used antidiabetic drug metformin has antineoplastic activity, but there are caveats. Although population studies suggest that metformin exposure is associated with reduced cancer risk and/or improved prognosis, these data are mostly retrospective and nonrandomized. Laboratory models show antineoplastic activity, but metformin concentrations used in many experiments exceed those achieved with conventional doses used for diabetes treatment. Ongoing translational research should be useful in guiding design of clinical trials, not only to evaluate metformin at conventional antidiabetic doses, where reduction of elevated insulin levels may contribute to antineoplastic activity for certain subsets of patients, but also to explore more aggressive dosing of biguanides, which may lead to reprogramming of energy metabolism in a manner that could provide important opportunities for synthetic lethality through rational drug combinations or in the context of genetic lesions associated with hypersensitivity to energetic stress. Significance: There are tantalizing clues that justify the investigation of antineoplastic activities of biguanides. The complexity of their biologic effects requires further translational research to guide clinical trial design. Cancer Discov; 2(9); 778–90. ©2012 AACR.

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Section: Effects At the Whole-organism Levelmentioning

confidence: 99%

Section: Identifying the Key Mechanisms Of Actionmentioning

confidence: 99%

Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning

2012

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“…Phenformin is 50-fold more potent than metformin as an inhibitor of mitochondrial complex 1 and being lipophilic (21) is less dependent on OCT (27), retaining the dose-dependent antiproliferative effect in ovarian cancer cell lines even in the presence of OCT1 siRNA (28). Given that oxidative phosphorylation-dependent production of ATP seems to be secondary to mitochondrial synthesis of anabolic precursors in proliferating cells (29), it has been suggested that metformin exerts the chemopreventive effects by functioning as a weak mitochondrial poison inhibiting oxidative phosphorylation (30).…”

Section: Mitochondrial Effectsmentioning

confidence: 99%

“…Biomarker studies built in to all these trials will be essential to identify the breast cancers with characteristics (such as the LKB1-AMPK or p53-defective pathways) most likely to be susceptible to the effects of metformin. Cancer heterogeneity of OCT1, and hence for cancer cell uptake of metformin, as observed in ovarian cancer (28), may merit measurement before considering metformin therapy in the clinical setting given, for example, the low expression of OCT1 in normal breast tissues. The potential effects of polymorphisms of LKB1, OCT 1,2,3, and ATM on resistance to metformin (70) and interactions between proton pump inhibitors and metformin via OCT 1,2,3 (70) will clearly need to be considered when metformin translates into routine clinical practice.…”

Section: Metformin and Breast Cancer Trialsmentioning

confidence: 99%

Molecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer

Thompson

2014

Clinical Cancer Research

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Metformin, an oral biguanide widely used to treat diabetes, has considerable potential and is in clinical trials as an experimental preventive or therapeutic agent for a range of cancers. Direct actions targeting cellular pathways, particularly via AMP-activated protein kinase and through inhibiting mitochondrial ATP synthesis, or systemic mechanisms involving insulin and insulin-like growth factors have been much studied in vitro and in preclinical models. Epidemiologic and retrospective studies also provide clinical evidence in support of metformin as an antitumor agent. Preoperative window-ofopportunity trials confirm the safety of metformin in women with primary breast cancer, and demonstrate reduction in tumor cell proliferation and complex pathways of gene suppression or overexpression attributable to metformin. Confirmation of insulin-mediated effects, independent of body mass index, also supports the potential benefit of adjuvant metformin therapy. Neoadjuvant, adjuvant, and advanced disease trials combining metformin with established anticancer agents are under way or proposed. Companion biomarker studies will utilize in vitro and preclinical understanding of the relevant molecular pathways to, in future, refine patient and tumor selection for metformin therapy. Clin Cancer Res; 20(10); 2508-15. Ó2014 AACR.

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“…It is possible that these inconsistencies may result from unrecognized genetic and/or metabolic characteristics of the tumor or the host that determine metformin sensitivity. Prior work has identified host insulin levels (10), LKB1 status (10), and expression of transport molecules for metformin uptake (33) as candidate predictors of metformin sensitivity. Here, we examined carbon source and myc expression as candidate predictive markers for antineoplastic activity of metformin.…”

Section: Introductionmentioning

confidence: 99%

Carbon Source and Myc Expression Influence the Antiproliferative Actions of Metformin

Javeshghani¹,

Zakikhani²,

Austin³

et al. 2012

Cancer Research

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Epidemiologic and experimental data have led to increased interest in possible roles of biguanides in cancer prevention and/or treatment. Prior studies suggest that the primary action of metformin is inhibition of oxidative phosphorylation, resulting in reduced mitochondrial ATP production and activation of AMPK. In vitro, this may lead to AMPK-dependent growth inhibition if AMPK and its effector pathways are intact or to an energetic crisis if these are defective. We now show that the effect of exposure of several transformed cell lines to metformin varies with carbon source: in the presence of glutamine and absence of glucose, a 75% decrease in cellular ATP and an 80% decrease in cell number is typical; in contrast, when glucose is present, metformin exposure leads to increased glycolysis, with only a modest reduction in ATP level and cell number. Overexpression of myc was associated with sensitization to the antiproliferative effects of metformin, consistent with myc involvement in "glutamine addiction". Our results reveal previously unrecognized factors that influence metformin sensitivity and suggest that metformin-induced increase in glycolysis attenuates the antiproliferative effects of the compound. Cancer Res; 72(23); 6257-67. Ó2012 AACR.

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Relevance of the OCT1 transporter to the antineoplastic effect of biguanides

Cited by 83 publications

References 25 publications

Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning

Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning

Molecular Pathways: Preclinical Models and Clinical Trials with Metformin in Breast Cancer

Carbon Source and Myc Expression Influence the Antiproliferative Actions of Metformin

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