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首页> 外文期刊>Journal of Cellular Physiology >Concentration‐dependent metabolic effects of metformin in healthy and Fanconi anemia lymphoblast cells
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Concentration‐dependent metabolic effects of metformin in healthy and Fanconi anemia lymphoblast cells

机译：浓度相关的代谢的影响二甲双胍在健康和Fanconi贫血成淋巴细胞的细胞

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摘要

Metformin (MET) is the drug of choice for patients with type 2 diabetes and has been proposed for use in cancer therapy and for treating other metabolic diseases. More than 14,000 studies have been published addressing the cellular mechanisms affected by MET. However, several in vitro studies have used concentrations of the drug 10–100‐fold higher than the plasmatic concentration measured in patients. Here, we evaluated the biochemical, metabolic, and morphologic effects of various concentrations of MET. Moreover, we tested the effect of MET on Fanconi Anemia (FA) cells, a DNA repair genetic disease with defects in energetic and glucose metabolism, as well as on human promyelocytic leukemia (HL60) cell lines. We found that the response of wild‐type cells to MET is concentration dependent. Low concentrations (15 and 150?μM) increase both oxidative phosphorylation and the oxidative stress response, acting on the AMPK/Sirt1 pathway, while the high concentration (1.5?mM) inhibits the respiratory chain, alters cell morphology, becoming toxic to the cells. In FA cells, MET was unable to correct the energetic/respiratory defect and did not improve the response to oxidative stress and DNA damage. By contrast, HL60 cells appear sensitive also at 150?μM. Our findings underline the importance of the MET concentration in evaluating the effect of this drug on cell metabolism and demonstrate that data obtained from in vitro experiments, that have used high concentrations of MET, cannot be readily translated into improving our understanding of the cellular effects of metformin when used in the clinical setting.
机译：二甲双胍(遇到)患者的首选药物2型糖尿病患者和已被提出了用在癌症治疗和其他治疗代谢疾病。发表在细胞机制受到影响。研究用药物的浓度10 - 100倍高于血浆的浓度测量的患者。评估了生化、代谢和不同浓度的形态学的影响满足。Fanconi贫血(FA)细胞,DNA修复基因疾病与缺陷在精力充沛和葡萄糖新陈代谢,以及人类早幼粒细胞白血病HL60细胞株。响应的野生类型细胞相遇浓度依赖性。和150年?μM)增加氧化磷酸化和氧化应激反应,作用于AMPK / Sirt1途径,高浓度(1.5 ?毫米)抑制了呼吸链,改变细胞形态,成为细胞毒性。无法正确的能量/呼吸缺陷,没有改进的响应氧化应激和DNA损伤。HL60细胞出现敏感也在150 ?μM。研究结果强调了的重要性集中在评估的影响药物对细胞代谢和显示数据从体外实验,获得的使用高浓度的满足,不能容易转化为改善我们的对细胞的影响的理解二甲双胍在临床使用时设置。

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