| Autor: |
Giuseppe Filomeni, Francesca De Maria, Paola Turella, Agnese Molinari, Maurizio Cianfriglia, Giorgio Federici, Maria Rosa Ciriolo, Marina Tombesi, Maria Luisa Dupuis, Anna Maria Caccuri, Giorgio Ricci |
| Rok vydání: |
2006 |
| Předmět: |
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| Zdroj: |
Journal of Biological Chemistry. 281:23725-23732 |
| ISSN: |
0021-9258 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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