title: 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.
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.
authors.affiliation: Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Turella
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Filomeni
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Dupuis
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Ciriolo
authors.forename: Agnese
authors.initials: A
authors.lastname: Molinari
authors.forename: Francesca
authors.initials: F
authors.lastname: De Maria
authors.forename: Marina
authors.initials: M
authors.lastname: Tombesi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cianfriglia
authors.forename: Giorgio
authors.initials: G
authors.lastname: Federici
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ricci
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Caccuri
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D000208:Acute Disease; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001692:Biological Transport / Q000187:drug effects; D020169:Caspases / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity*; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors*; D006801:Humans; D007700:Kinetics; D015458:Leukemia, T-Cell / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity*; D010641:Phenotype; D010879:Piperazines / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity*
chemical_list: C432126:4-nitro-7-piperazino-2,1,3-benzoxadiazole; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D010879:Piperazines; D005982:Glutathione Transferase; D020169:Caspases