Mitochondrial electron transport chain activity, but not ATP synthesis, is required for drug‐induced apoptosis in human leukaemic cells: a possible novel mechanism of regulating drug resistance

• Published in: British journal of haematology Vol. 98; no. 3; pp. 686 - 698
• Main Authors: Jia, Li, Allen, Paul D., Macey, Marion G., Grahn, Michael F., Newland, Adrian C., Kelsey, Stephen M.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-09-1997; Blackwell
• Subjects: Adenosine Triphosphatases - antagonists & inhibitors; Adenosine Triphosphate - biosynthesis; Antineoplastic agents; Antineoplastic Agents, Phytogenic - therapeutic use; Apoptosis - drug effects; Biological and medical sciences; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Electron Transport; F1F0‐ATPase; General aspects; Glucose - metabolism; Humans; Lactic Acid - metabolism; Leukemia-Lymphoma, Adult T-Cell - drug therapy; Leukemia-Lymphoma, Adult T-Cell - metabolism; Leukemia-Lymphoma, Adult T-Cell - pathology; Medical sciences; Mitochondria - metabolism; mitochondrial electron transport chain (ETC); multidrug resistance (MDR); Oligomycins - pharmacology; Pharmacology. Drug treatments; P‐glycoprotein (Pgp); Tumor Cells, Cultured; vinblastine; Vinblastine - therapeutic use; Antineoplastic agent; Human; P Glycoprotein; Malignant hemopathy; In vitro; Mechanism; Electron carrier; Mitochondria; Enzymatic activity; Cell death; Multiple resistance; Established cell line; T-Lymphocyte; Acute lymphocytic leukemia; Negative therapeutic reaction; Apoptosis
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1046/j.1365-2141.1997.2683085.x

There is increasing evidence for an association between mitochondrial function and susceptibility to apoptosis. It has been shown that the vinblastine‐resistant leukaemic cell line CEM/VLB100 has a more active mitochondrial electron transport chain (ETC) than the parental CCRF‐CEM cell line. Inhibition of mitochondrial DNA replication by ethidium bromide (EB) depleted the activity of the ETC and reduced cellular respiratory rate. Depletion of mitochondrial DNA was associated with increased resistance to vinblastine‐induced apoptosis in both cell lines. In contrast, the highly specific inhibitor of the energy producing mitochondrial enzyme F1F0‐ATPase, oligomycin, rendered CEM/VLB100 cells more sensitive to vinblastine by inhibiting the energy‐dependent P‐glycoprotein (Pgp) pump, suggesting that the effect of EB is independent of energy generation and ATPase activity. Both mitochondrial ETC depletion and ATPase inhibition decreased vinblastine‐induced cell cycle changes in the CCRF‐CEM cell line, suggesting that cell cycle changes are dependent on ATP generation. However, EB‐induced ETC depletion in CEM/VLB100 cells inhibited apoptosis in response to high concentration of vinblastine, but not G2M arrest. We suggest that: (1) over‐expression of Pgp by drug‐resistant cells may up‐regulate mitochondrial energy production; (2) mitochondrial ETC activity is required for DNA fragmentation in response to vinblastine, but the mechanism is independent of Pgp activity and ATP generation; (3) down‐regulation of mitochondrial ETC activity may confer resistance to vinblastine‐induced apoptosis; (4) the mitochondrial ETC is involved in vinblastine‐induced apoptosis downstream of microtubule disruption and cell cycle changes.