Doxorubicin increases oxidative metabolism in HL-1 cardiomyocytes as shown by 13C metabolic flux analysis.
Doxorubicin increases oxidative metabolism in HL-1 cardiomyocytes as shown by 13C metabolic flux analysis.
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如 13C 代谢流分析所示，Doxorubicin 会增加 HL-1 心肌细胞的氧化代谢。
DOI：
10.1093/toxsci/kfr298
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
F. Noor
中科院分区：
文献类型：
--
作者：
Alexander Strigun;J. Wahrheit;J. Niklas;E. Heinzle;F. Noor
阿霉素（DXR）是一种抗癌药物，由于严重的心脏毒性作用，其使用受到限制。这些影响部分是由心肌能量代谢紊乱引起的。我们分析了治疗相关但无毒的DXR浓度对代谢通量、细胞呼吸和细胞内ATP的影响。(13)C使用[U-（13）C（6）]葡萄糖、[1，2-（13）C（2）]葡萄糖和[U-（13）C（5）]谷氨酰胺对暴露于0.01和0.02 μM DXR的HL-1心肌细胞进行同位素标记研究，并与未处理的对照组进行比较。通过将细胞外代谢物（葡萄糖、乳酸、丙酮酸和氨基酸）的产生和摄取速率以及源自各自（13）C-标记底物的分泌乳酸中的（13）C-标记整合到代谢网络模型中来计算代谢通量。研究的DXR浓度（0.01和0.02 μM）对HL-1心肌细胞的细胞活力和搏动没有影响。糖酵解通量显着减少在测试DXR浓度处理的细胞。氧化代谢显著增加（更高的葡萄糖氧化、氧化脱羧、TCA循环速率和呼吸），表明葡萄糖碳的利用更有效。这些变化伴随着细胞内ATP的减少。我们的结论是，DXR在纳摩尔范围内显着改变HL-1心肌细胞的中心碳代谢，这导致更高的耦合糖酵解和TCA循环。肌细胞可能试图补偿减少的细胞内ATP，这反过来可能是由于通过形成活性氧或电子分流损失NADH电子的结果。
Doxorubicin (DXR), an anticancer drug, is limited in its use due to severe cardiotoxic effects. These effects are partly caused by disturbed myocardial energy metabolism. We analyzed the effects of therapeutically relevant but nontoxic DXR concentrations for their effects on metabolic fluxes, cell respiration, and intracellular ATP. (13)C isotope labeling studies using [U-(13)C(6)]glucose, [1,2-(13)C(2)]glucose, and [U-(13)C(5)]glutamine were carried out on HL-1 cardiomyocytes exposed to 0.01 and 0.02 μM DXR and compared with the untreated control. Metabolic fluxes were calculated by integrating production and uptake rates of extracellular metabolites (glucose, lactate, pyruvate, and amino acids) as well as (13)C-labeling in secreted lactate derived from the respective (13)C-labeled substrates into a metabolic network model. The investigated DXR concentrations (0.01 and 0.02 μM) had no effect on cell viability and beating of the HL-1 cardiomyocytes. Glycolytic fluxes were significantly reduced in treated cells at tested DXR concentrations. Oxidative metabolism was significantly increased (higher glucose oxidation, oxidative decarboxylation, TCA cycle rates, and respiration) suggesting a more efficient use of glucose carbon. These changes were accompanied by decrease of intracellular ATP. We conclude that DXR in nanomolar range significantly changes central carbon metabolism in HL-1 cardiomyocytes, which results in a higher coupling of glycolysis and TCA cycle. The myocytes probably try to compensate for decreased intracellular ATP, which in turn may be the result of a loss of NADH electrons via either formation of reactive oxygen species or electron shunting.
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影响因子：
15.9
作者：
WISNESKI, JA;GERTZ, EW;CRAIG, JC
通讯作者：
CRAIG, JC
影响因子：
37.8
作者：
J. C. Gomez
通讯作者：
J. C. Gomez
影响因子：
8.4
作者：
Antoniewicz, Maciek R.;Kelleher, Joanne K.;Stephanopoulos, Gregory
通讯作者：
Stephanopoulos, Gregory
DOI：
10.1073/pnas.95.6.2979
发表时间：
1998-03-17
影响因子：
11.1
作者：
Claycomb, WC;Lanson, NA;Izzo, NJ
通讯作者：
Izzo, NJ
DOI：
10.1152/ajpheart.2001.281.4.h1613
发表时间：
2001-10-01
影响因子：
4.8
作者：
Panchal, AR;Comte, B;Stanley, WC
通讯作者：
Stanley, WC