Mechanisms of Anthracycline-Enhanced Reactive Oxygen Metabolism in Tumor Cells
Mechanisms of Anthracycline-Enhanced Reactive Oxygen Metabolism in Tumor Cells
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DOI：
10.1155/2019/9474823
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发表时间：
2019-12-03
影响因子：
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通讯作者：
Doroshow, James H.
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文献类型：
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作者：
Doroshow, James H.
在这项研究中，我们研究了蒽环类抗生素对埃利希肿瘤细胞氧自由基代谢的影响。在肿瘤微粒体和细胞核中，多柔比星以剂量依赖性方式增加超氧阴离子的产生，似乎遵循饱和动力学;这些细胞器形成超氧阴离子的表观Km和Vmax分别为124.9 μ M和22.6 nmol/min/mg和103.4 μ M和4.8 nmol/min/mg。在肿瘤微粒体和细胞核中，超氧化物的形成需要NADPH作为辅因子，伴随着过氧化氢的形成，并且是通过NADPH：细胞色素P-450还原酶（NADPH：铁细胞色素氧化还原酶，EC 1.6.2.4）将电子从NADPH转移到多柔比星醌的结果。蒽环类抗生素也显着增强超氧阴离子的产生肿瘤线粒体与表观Km和Vmax阿霉素的123.2 μ M和14.7 nmol/min/mg。然而，药物刺激的线粒体产生超氧化物需要NADH，并增加鱼藤酮，这表明在肿瘤细胞中的电子传递链的近端部分是负责减少阿霉素醌在这个网站。药物相关的氧自由基产生的净速率也确定为完整的埃利希肿瘤细胞，在这个系统中，治疗与阿霉素产生了剂量相关的增加抗氰呼吸，增强细胞内还原当量的变化。最后，我们发现，在铁的存在下，治疗与阿霉素显着增加甲醛的生产从二甲亚砜，表明羟基自由基可以产生完整的肿瘤细胞后蒽环类药物暴露。这些实验表明，蒽环类抗生素能够显著增强埃利希肿瘤细胞中多个细胞内位点的氧自由基代谢，其反应可能导致这类药物的细胞毒性。
In this investigation, we examined the effect of anthracycline antibiotics on oxygen radical metabolism in Ehrlich tumor cells. In tumor microsomes and nuclei, doxorubicin increased superoxide anion production in a dose-dependent fashion that appeared to follow saturation kinetics; the apparent Km and Vmax for superoxide formation by these organelles was 124.9 mu M and 22.6 nmol/min/mg, and 103.4 mu M and 4.8 nmol/min/mg, respectively. In both tumor microsomes and nuclei, superoxide formation required NADPH as a cofactor, was accompanied by the formation of hydrogen peroxide, and resulted from the transfer of electrons from NADPH to the doxorubicin quinone by NADPH:cytochrome P-450 reductase (NADPH:ferricytochrome oxidoreductase, EC 1.6.2.4). Anthracycline antibiotics also significantly enhanced superoxide anion production by tumor mitochondria with an apparent Km and Vmax for doxorubicin of 123.2 mu M and 14.7 nmol/min/mg. However, drug-stimulated superoxide production by mitochondria required NADH and was increased by rotenone, suggesting that the proximal portion of the electron transport chain in tumor cells was responsible for reduction of the doxorubicin quinone at this site. The net rate of drug-related oxygen radical production was also determined for intact Ehrlich tumor cells; in this system, treatment with doxorubicin produced a dose-related increase in cyanide-resistant respiration that was enhanced by changes in intracellular reducing equivalents. Finally, we found that in the presence of iron, treatment with doxorubicin significantly increased the production of formaldehyde from dimethyl sulfoxide, an indication that the hydroxyl radical could be produced by intact tumor cells following anthracycline exposure. These experiments suggest that the anthracycline antibiotics are capable of significantly enhancing oxygen radical metabolism in Ehrlich tumor cells at multiple intracellular sites by reactions that could contribute to the cytotoxicity of this class of drugs.