Increased activity and sensitivity of mitochondrial respiratory enzymes to tumor necrosis factor alpha-mediated inhibition is associated with increased cytotoxicity in drug-resistant leukemic cell lines
Increased activity and sensitivity of mitochondrial respiratory enzymes to tumor necrosis factor alpha-mediated inhibition is associated with increased cytotoxicity in drug-resistant leukemic cell lines
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DOI：
10.1182/blood.v87.6.2401.bloodjournal8762401
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发表时间：
1996-03-15
期刊：
影响因子：
20.3
通讯作者：
Newland, AC
中科院分区：
文献类型：
--
作者：
Jia, L;Kelsey, SM;Newland, AC
与其亲本细胞系 CCRF-CEM 和 K562 cl.6 相比，耐药白血病细胞系 CEM/VLB(100) 和 K/DAU(600) 对肿瘤坏死因子 α (TNF α) 介导的细胞毒性更敏感。耐药白血病细胞系具有更活跃的线粒体功能，这与对 TNF α 诱导的呼吸抑制更敏感有关。 TNF α 阻断三个位点的电子转移：NADH 脱氢酶（复合物 I）、琥珀酸脱氢酶（复合物 II）和细胞色素 c 氧化酶（复合物 IV）。在耐药、TNF 敏感细胞系中，呼吸频率和电子传递链酶活性受到显着抑制。呼吸抑制发生在细胞死亡之前至少 5 至 8 小时。呼吸衰竭不能通过糖酵解途径的适当上调来补偿。通过长期培养 2 mmol/L 5'-二磷酸腺苷 (ADP) 和 Pi，增加线粒体呼吸频率和酶活性，使药物敏感和耐药细胞对 TNF α 诱导的细胞溶解敏感。与 TNF α 的作用相比，百草枯产生的线粒体内自由基对呼吸抑制和细胞溶解作用仅具有有限且延迟的作用。我们得出的结论是，TNF α 在白血病细胞中诱导的细胞毒性至少部分是由线粒体呼吸抑制介导的。 TNF α 产生的自由基可能不会直接导致观察到的线粒体电子传递抑制，并且必须涉及其他机制。 (C) 1996 年，美国血液学会。
The drug-resistant leukemic cell lines, CEM/VLB(100) and K/DAU(600), are more sensitive to tumor necrosis factor alpha (TNF alpha)-mediated cytotoxicity compared with their parental cell lines, CCRF-CEM and K562 cl.6. Drug-resistant leukemic cell lines have more active mitochondrial function, which is associated with a greater susceptibility to TNF alpha-induced respiratory inhibition. TNF alpha blocked electron transfer at three sites, NADH dehydrogenase (complex I), succinate dehydrogenase (complex II), and cytochrome c oxidase (complex IV). Respiratory rate and electron transport chain enzyme activities were significantly inhibited in the drug-resistant, TNF-sensitive cell lines. Respiratory inhibition preceded cell death by at least 5 to 8 hours. The respiratory failure was not compensated for by appropriate up-regulation of the glycolytic pathway. Increasing mitochondrial respiratory rate and enzyme activities by long-term culture with 2 mmol/L adenosine 5'-diphosphate (ADP) and Pi sensitized both drug-sensitive and drug-resistant cells to TNF alpha-induced cytolysis. Intramitochondrial free radicals generated by paraquat only had a limited and delayed effect on respiratory inhibition and cytolysis in comparison with the effect of TNF alpha. We conclude that TNF alpha-induced cytotoxicity in leukemic cells is, at least in part, mediated by inhibition of mitochondrial respiration. Free radical generation by TNF alpha may not directly lead to the observed inhibition of the mitochondrial electron transport and other mechanisms must be involved. (C) 1996 by The American Society of Hematology.