title: Proapoptotic activity of new glutathione S-transferase inhibitors.
abstract: Selected 7-nitro-2,1,3-benzoxadiazole derivatives have been recently found very efficient inhibitors of glutathione S-transferase (GST) P1-1, an enzyme which displays antiapoptotic activity and is also involved in the cellular resistance to anticancer drugs. These new inhibitors are not tripeptide glutathione-peptidomimetic molecules and display lipophylic properties suitable for crossing the plasma membrane. In the present work, we show the strong cytotoxic activity of these compounds in the following four different cell lines: K562 (human myeloid leukemia), HepG2 (human hepatic carcinoma), CCRF-CEM (human T-lymphoblastic leukemia), and GLC-4 (human small cell lung carcinoma). The LC50 values are in the micromolar/submicromolar range and are close to the IC50 values obtained with GSTP1-1, suggesting that the target of these molecules inside the cell is indeed this enzyme. The cytotoxic mechanism of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol, the most effective GSTP1-1 inhibitor, has been carefully investigated in leukemic CCRF-CEM and K562 cell lines. Western blot and immunoprecipitation analyzes have shown that 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol promotes in both cell lines the dissociation of the GSTP1-1 in a complex with c-jun NH2-terminal kinase (JNK). This process triggers a reactive oxygen species (ROS)-independent activation of the JNK-mediated pathway that results in a typical process of apoptosis. Besides this main pathway, in K562 cells, a ROS-mediated apoptosis partially occurs (about 30%) which involves the p38MAPK signal transduction pathway. The low concentration of this new compound needed to trigger cytotoxic effects on tumor cells and the low toxicity on mice indicate that the new 7-nitro-2,1,3-benzoxadiazole derivatives are promising anticancer agents.
authors.affiliation: Department of Chemical Sciences and Technologies, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Turella
authors.forename: Claudia
authors.initials: C
authors.lastname: Cerella
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Filomeni
authors.forename: Angela
authors.initials: A
authors.lastname: Bullo
authors.forename: Francesca
authors.initials: F
authors.lastname: De Maria
authors.forename: Lina
authors.initials: L
authors.lastname: Ghibelli
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Ciriolo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cianfriglia
authors.forename: Maurizio
authors.initials: M
authors.lastname: Mattei
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: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020014:K562 Cells; D015458:Leukemia, T-Cell / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D010069:Oxadiazoles / Q000494:pharmacology*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010069:Oxadiazoles; D017382:Reactive Oxygen Species; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; C496557:Gstp1 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases