Metformin Pharmacokinetics in Mouse Tumors: Implications for Human Therapy

Dowling, Ryan J.O.; Lam, Sonya H.L.; Bassi, C.; Mouaaz, Samar; Aman, Ahmed; Kiyota, Taira; Al‐awar, Rima; Goodwin, Pamela J.; Stambolic, Vuk

doi:10.1016/j.cmet.2016.03.006

Cited by 107 publications

(126 citation statements)

References 10 publications

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“…6a-c), consistent with metformin pharmacokinetics in other tumour-bearing mice given metformin in drinking water 17,18 . No difference in serum glucose and lactate levels were seen (Extended Data Fig.…”

supporting

confidence: 58%

“…Our study suggests that the metformin levels achieved in our GEMMs were too low to inhibit tumour growth. Although the metformin doses used here were comparable with clinically effective doses for diabetes treatment in humans, species differences in the pharmacodynamics and/or pharmacokinetics of metformin could make it difficult to translate these responses from mouse to humans 17,18 . While the response to metformin is dose-dependent, our data support the results of in vitro studies that show that manipulating ROS can modulate the response of tumours to SG starvation 7 .…”

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confidence: 99%

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Modulating the therapeutic response of tumours to dietary serine and glycine starvation

Maddocks

Athineos

Cheung

et al. 2017

Nature

485

399

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Maddocks, O. D. K. et al. (2017) Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature, 544(7650), pp. 372-376.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/140432/ AbstractThe non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1). While some cancer cells upregulate de novo serine synthesis 2,3,4 , many others rely on exogenous serine for optimal growth 5,6,7 . Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models 7,8 . Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Krasdriven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis.To assess the effect of dietary serine and glycine (SG) restriction in autochthonous tumour models, we used genetically engineered mouse models (GEMMs) of lymphoma (Eμ-Myc) and intestinal tumours (defective Apc). Eμ-Myc mice develop pre-neoplastic lesions within 28-42 days after birth 9 , and adenoma initiation is evident days after birth in Apc Min/+ mice 10 . Accordingly, Apc Min/+ mice carried high tumour numbers at 80 days, which subsequently increased in size but not number (Extended Data Fig. 1a). Transferring mice from normal chow diet to experimental diets 60-80 days after birth showed that an SG-free diet significantly extended survival in these models carrying pre-malignant lesions (Fig. 1a, b), with a slightly lower tumour burden in Apc Min/+ mice on the SG-free diet at clinical end point (Extended Data Fig. 1a). The diet reproducibly decreased serum SG from around 150 μM to 65 μM (Fig. 1c-e), while showing minimal or inconsistent impact on other amino acids, glucose and lactate (Fig. 1c, d and Extended Data Figs 1b, 2a, b), These results were further validated using an inducible intestinal tumour model (Lgr5-creER;Apc fl/fl ); transferring mice to the SG-free diet a week after induction. Again, the experimental diet caused a significant increase in survival compared to control diet (containing purified amino acids) or normal chow (containing whole protein as a source of amino acids) (Fig. 1f). (c, control, n = 14; control,...

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supporting

confidence: 58%

mentioning

confidence: 99%

Modulating the therapeutic response of tumours to dietary serine and glycine starvation

Maddocks

Athineos

Cheung

et al. 2017

Nature

485

399

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“…Therefore, further preclinical pharmacokinetics studies of MetF coadministered with the first-line antitubercular regimen are urgently needed to guide the future study of this promising agent in clinical trials (19,20). In addition, detailed pharmacodynamics studies are required to relate plasma drug exposures in mice to AMPK activation and anti-TB activity in cell culture systems (6,21). Finally, it is important to recognize that observations made in the mouse model are not necessarily predictive of outcomes in clinical trials of TB treatment nor is early "sterilization" a predictor of cure in humans (22).…”

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confidence: 99%

Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

Dutta

Pinn

Karakousis

2017

Antimicrob Agents Chemother

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Preliminary preclinical and observational studies suggest the potential utility of metformin as an adjunctive, host-directed agent for treatment of tuberculosis (TB). In this study, we sought to investigate the bactericidal and sterilizing activities of human-like exposures of metformin when given in combination with the firstline regimen against chronic tuberculosis in BALB/c mice. Mice receiving metformin adjunctive therapy had similar lung bacillary burdens with control mice during treatment, and the proportion of mice with microbiological relapse was similar between the two groups.KEYWORDS Mycobacterium tuberculosis, metformin, standard first-line regimen, BALB/c, bactericidal, sterilizing, host-directed therapy, relapse, cure, Denver regimen H ost-directed therapy (HDT) may offer expanded therapeutic options for improving tuberculosis (TB) treatment (1-5). Metformin (MetF), an AMP-activated protein kinase (AMPK)-activating drug for type 2 diabetes (DM), was reported to inhibit intracellular growth of mycobacteria by inducing reactive oxygen species and to enhance the efficacy of conventional anti-TB drugs in mouse models of acute and chronic TB; its use was associated with decreased TB severity and improved clinical outcomes in a retrospective analysis of 220 patients with DM and TB (6). In another retrospective study, Srujitha et al. showed that MetF use was associated with a 3.9-fold reduction in TB incidence among patients with DM (7). Based on these findings, we hypothesized that MetF adjunctive therapy would enhance the bactericidal and sterilizing activities of the standard first-line treatment (8, 9) against chronic TB infection in mice and shorten the duration of curative treatment as assessed by microbiological relapse.All animal-related procedures were approved by the Johns Hopkins University (JHU) School of Medicine Animal Care and Use Committee. A total of 170 female BALB/c mice aged 4 to 6 weeks (Charles River Labs, Wilmington, MA) were aerosol infected with Mycobacterium tuberculosis H37Rv (JHU) using the inhalation exposure system (GlasCol, Terre Haute, IN) calibrated to deliver ϳ10 2 CFU per mouse lung in two consecutive runs. After aerosol infection, the mice were randomized into the two treatment groups. Six weeks postinfection, the mice were treated daily (5 days/week) via esophageal cannulation with human-equivalent doses of rifampin (10 mg/kg), isoniazid (10 mg/kg), pyrazinamide (150 mg/kg), and ethambutol (100 mg/kg) (RHZE) with or without MetF (250 mg/kg) for up to 6 months (2, 10, 11). For the first 2 months of treatment, the mice received RHZE and, for the remaining 4 months, only rifampin and isoniazid (RH) to mirror the first-line regimen in humans. The rifampin dose preceded that of the other drugs by at least 1 h to prevent pharmacokinetic antagonism (12, 13). The dose of MetF (6) and is estimated (14) to be equivalent to 25 mg/kg in humans (15), which is well tolerated (15, 16). Groups of 5 mice were sacrificed on the day after infection, on the day of treatment initi...

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“…That metformin could not entirely restore the abundance of H3K27me3 occurring in the liver of HFD‐fed animals (Vella et al., 2013) might reflect the epigenetic incapacity of HFD‐damaged tissues to fully benefit from the expected response to metformin unless combined with diet reversal (Riera‐Borrull et al., 2017). At a dose of 250 mg kg −1 day −1 i.p., a route of administration that is equivalent to 1,200 mg/day metformin for a 60 kg individual (Reagan‐Shaw, Nihal & Ahmad, 2008) and yields plasma concentrations in the low micromolar range (Chandel et al., 2016; Dowling et al., 2016; Memmott et al., 2010; Menendez, Martin‐Castillo & Joven, 2016), metformin treatment resulted in a significant twofold reduction in the tumor volume in xenograft‐bearing mice highly enriched with tumor‐initiating cancer stem cells (CSC) (Cufi et al., 2012; Martin‐Castillo et al., 2013; Oliveras‐Ferraros et al., 2012) that was accompanied by a noteworthy twofold augmentation of global H3K27me3 in tumor tissues. Because decreased abundance of H3K27me3 is a predictor of cancer aggressiveness independently of the expression of the H3K27me3 methyltransferase EZH2 (Holm et al., 2012; Wei et al., 2008) closely related to the maintenance of poorly differentiated CSC (Sakaki et al., 2015; Yan et al., 2017), our findings suggest that metformin might exert a suppressive influence on the CSC phenotype by enhancing deposition of the repressive H3K27me3 mark.…”

Section: Discussionmentioning

confidence: 99%

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

et al. 2018

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SummaryMetformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants. We here outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. Using several structure‐ and ligand‐based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as the member of the H3K27me3‐specific demethylase subfamily, KDM6A/UTX. AlphaScreen and AlphaLISA assays confirmed the ability of metformin to inhibit the demethylation activity of purified KDM6A/UTX enzyme. Structural studies revealed that metformin might occupy the same set of residues involved in H3K27me3 binding and demethylation within the catalytic pocket of KDM6A/UTX. Millimolar metformin augmented global levels of H3K27me3 in cultured cells, including reversion of global loss of H3K27me3 occurring in premature aging syndromes, irrespective of mitochondrial complex I or AMPK. Pharmacological doses of metformin in drinking water or intraperitoneal injection significantly elevated the global levels of H3K27me3 in the hepatic tissue of low‐density lipoprotein receptor‐deficient mice and in the tumor tissues of highly aggressive breast cancer xenograft‐bearing mice. Moreover, nondiabetic breast cancer patients receiving oral metformin in addition to standard therapy presented an elevated level of circulating H3K27me3. Our biocomputational approach coupled to experimental validation reveals that metformin might directly regulate the biological machinery of aging by targeting core chromatin modifiers of the epigenome.

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Metformin Pharmacokinetics in Mouse Tumors: Implications for Human Therapy

Cited by 107 publications

References 10 publications

Modulating the therapeutic response of tumours to dietary serine and glycine starvation

Modulating the therapeutic response of tumours to dietary serine and glycine starvation

Metformin Adjunctive Therapy Does Not Improve the Sterilizing Activity of the First-Line Antitubercular Regimen in Mice

Metformin directly targets the H3K27me3 demethylase KDM6A/UTX

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