Selected 7-nitro-2,1,3-benzoxadiazole derivatives have been recently found very efficient inhibitors of glutathione S-transferase (GST) PI-1,(5) 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 ICs values obtained with GSTPI-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 GSTPI-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)hexanoI promotes in both cell lines the dissociation of the GSTPI-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 p38(MAPK) 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.

Turella, P., Cerella, C., Filomeni, G., Bullo, A., De Maria, F., Ghibelli, L., et al. (2005). Proapoptotic activity of new glutathione S-transferase inhibitors. CANCER RESEARCH, 65(9), 3751-3761 [10.1158/0008-5472.CAN-04-3903].

Proapoptotic activity of new glutathione S-transferase inhibitors

Filomeni, G;GHIBELLI, LINA;CIRIOLO, MARIA ROSA;MATTEI, MAURIZIO;FEDERICI, GIORGIO;RICCI, GIORGIO;CACCURI, ANNA MARIA
2005-01-01

Abstract

Selected 7-nitro-2,1,3-benzoxadiazole derivatives have been recently found very efficient inhibitors of glutathione S-transferase (GST) PI-1,(5) 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 ICs values obtained with GSTPI-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 GSTPI-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)hexanoI promotes in both cell lines the dissociation of the GSTPI-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 p38(MAPK) 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.
2005
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/10 - BIOCHIMICA
English
Con Impact Factor ISI
6 (7 nitro 2,1,3 benzoxadiazol 4 ylthio)hexanol; 7 nitro 2,1,3 benzoxadiazole derivative; antineoplastic agent; caspase; enzyme inhibitor; glutathione transferase; glutathione transferase inhibitor; mitogen activated protein kinase p38; reactive oxygen metabolite; stress activated protein kinase; unclassified drug; animal experiment; antineoplastic activity; apoptosis; article; cancer cell culture; cell membrane; cell strain ccrf cem; cell strain GLC 4; cell strain HepG2; cell strain K 562; controlled study; drug cytotoxicity; drug mechanism; human; human cell; lipophilicity; liver carcinoma; lung small cell cancer; lymphatic leukemia; male; mouse; myeloid leukemia; nonhuman; priority journal; signal transduction; Western blotting; Animals; Apoptosis; Carcinoma, Small Cell; Cell Line, Tumor; Enzyme Activation; Enzyme Inhibitors; Glutathione S-Transferase pi; Glutathione Transferase; Humans; Isoenzymes; JNK Mitogen-Activated Protein Kinases; K562 Cells; Leukemia, T-Cell; Liver Neoplasms; Lung Neoplasms; Male; Mice; Oxadiazoles; Oxidation-Reduction; p38 Mitogen-Activated Protein Kinases; Reactive Oxygen Species
Turella, P., Cerella, C., Filomeni, G., Bullo, A., De Maria, F., Ghibelli, L., et al. (2005). Proapoptotic activity of new glutathione S-transferase inhibitors. CANCER RESEARCH, 65(9), 3751-3761 [10.1158/0008-5472.CAN-04-3903].
Turella, P; Cerella, C; Filomeni, G; Bullo, A; De Maria, F; Ghibelli, L; Ciriolo, Mr; Cianfriglia, M; Mattei, M; Federici, G; Ricci, G; Caccuri, Am
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/38357
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