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A strong glutathione S-transferase inhibitor overcomes the P-glycoprotein-mediated resistance in tumor cells. 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) triggers a caspase-dependent apoptosis in MDR1-expressing leukemia cells.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2006 Aug 18; Vol. 281 (33), pp. 23725-32. Date of Electronic Publication: 2006 Jun 12. - Publication Year :
- 2006
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Abstract
- The new glutathione S-transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) is cytotoxic toward P-glycoprotein-overexpressing tumor cell lines, i.e. CEM-VBL10, CEM-VBL100, and U-2 OS/DX580. The mechanism of cell death triggered by NBDHEX has been deeply investigated in leukemia cell lines. Kinetic data indicate a similar NBDHEX membrane permeability between multidrug resistance cells and their sensitive counterpart revealing that NBDHEX is not a substrate of the P-glycoprotein export pump. Unexpectedly, this molecule promotes a caspase-dependent apoptosis that is unusual in the P-glycoprotein-overexpressing cells. The primary event of the apoptotic pathway is the dissociation of glutathione S-transferase P1-1 from the complex with c-Jun N-terminal kinase. Interestingly, leukemia MDR1-expressing cells show lower LC50 values and a higher degree of apoptosis and caspase-3 activity than their drug-sensitive counterparts. The increased susceptibility of the multidrug resistance cells toward the NBDHEX action may be related to a lower content of glutathione S-transferase P1-1. Given the low toxicity of NBDHEX in vivo, this compound may represent an attractive basis for the selective treatment of MDR1 P-glycoprotein-positive tumors.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily B, Member 1 biosynthesis
Acute Disease
Antineoplastic Agents pharmacology
Apoptosis physiology
Biological Transport drug effects
Cell Death drug effects
Cell Line, Tumor
Drug Resistance, Multiple drug effects
Drug Resistance, Neoplasm drug effects
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors metabolism
Humans
Kinetics
Leukemia, T-Cell metabolism
Mitochondria drug effects
Mitochondria enzymology
Mitochondria physiology
Oxadiazoles chemical synthesis
Oxadiazoles metabolism
Phenotype
Piperazines chemical synthesis
Piperazines metabolism
ATP Binding Cassette Transporter, Subfamily B, Member 1 physiology
Apoptosis drug effects
Caspases physiology
Enzyme Inhibitors toxicity
Glutathione Transferase antagonists & inhibitors
Leukemia, T-Cell enzymology
Leukemia, T-Cell pathology
Oxadiazoles toxicity
Piperazines toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 281
- Issue :
- 33
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 16769721
- Full Text :
- https://doi.org/10.1074/jbc.M604372200