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

Paola Turella, Giuseppe Filomeni, Maria Luisa Dupuis, Maria Rosa Ciriolo, Agnese Molinari, Francesca De Maria, Marina Tombesi, Maurizio Cianfriglia, Giorgio Federici, Giorgio Ricci, Anna Maria Caccuri

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)23725-23732
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number33
DOIs
Publication statusPublished - Aug 18 2006

ASJC Scopus subject areas

  • Biochemistry

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