Increased Activity and Sensitivity of Mitochondrial Respiratory Enzymes to Tumor Necrosis Factor α-Mediated Inhibition Is Associated With Increased Cytotoxicity in Drug-Resistant Leukemic Cell Lines

• Published in: Blood Vol. 87; no. 6; pp. 2401 - 2410
• Main Authors: Jia, Li, Kelsey, Stephen M., Grahn, Michael F., Jiang, Xu-Rong, Newland, Adrian C.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.03.1996; The Americain Society of Hematology
• Subjects: Adenosine Diphosphate - pharmacology; Antineoplastic agents; Biological and medical sciences; Cell Death; Cells, Cultured; Daunorubicin - pharmacology; Depression, Chemical; Drug Resistance, Neoplasm; Electron Transport - drug effects; Electron Transport Complex II; Electron Transport Complex IV - antagonists & inhibitors; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - toxicity; Free Radicals; General aspects; Glycolysis; Humans; Leukemia - pathology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology; Leukemia-Lymphoma, Adult T-Cell - pathology; Medical sciences; Mitochondria - drug effects; Mitochondria - enzymology; Multienzyme Complexes - antagonists & inhibitors; NAD(P)H Dehydrogenase (Quinone) - antagonists & inhibitors; Neoplasm Proteins - analysis; Oxidoreductases - antagonists & inhibitors; Paraquat - pharmacology; Pharmacology. Drug treatments; Succinate Dehydrogenase - antagonists & inhibitors; Superoxides - metabolism; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - pharmacology; Tumor Necrosis Factor-alpha - toxicity; Vinblastine - pharmacology; Antineoplastic agent; Human; Mitochondria; Leukemia; Cytokine; Established cell line; Cytotoxicity; Malignant hemopathy; In vitro; Negative therapeutic reaction; Biological activity; Tumor necrosis factor α
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V87.6.2401.bloodjournal8762401

The drug-resistant leukemic cell lines, CEM/VLB100 and K/DAU500, are more sensitive to tumor necrosis factor α (TNFα)-mediated cytotoxicity compared with their parental cell lines, CCRF-CEM and K562 c1.6. Drug-resistant leukemic cell lines have more active mitochondrial function, which is associated with a greater susceptibility to TNFα-induced respiratory inhibition. TNFα 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 TNFα-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 TNFα. We conclude that TNFα-induced cytotoxicity in leukemic cells is, at least in part, mediated by inhibition of mitochondrial respiration. Free radical generation by TNFα may not directly lead to the observed inhibition of the mitochondrial electron transport and other mechanisms must be involved.