Proapoptotic activity of new glutathione S-transferase inhibitors

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 g...

Full description

Saved in:

Bibliographic Details
Published in:	Cancer research (Chicago, Ill.) Vol. 65; no. 9; pp. 3751 - 3761
Main Authors:	TURELLA, Paola, CERELLA, Claudia, RICCI, Giorgio, CACCURI, Anna Maria, FILOMENI, Giuseppe, BULLO, Angela, DE MARIA, Francesca, GHIBELLI, Lina, CIRIOLO, Maria Rosa, CIANFTIGLIA, Maurizio, MANEI, Maurizio, FEDERICI, Giorgio
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 01-05-2005
Subjects:	Animals Antineoplastic agents Apoptosis - drug effects Apoptosis - physiology Biological and medical sciences Carcinoma, Small Cell - drug therapy Carcinoma, Small Cell - enzymology Carcinoma, Small Cell - pathology Cell Line, Tumor Enzyme Activation - drug effects Enzyme Inhibitors - pharmacology Glutathione S-Transferase pi Glutathione Transferase - antagonists & inhibitors Humans Isoenzymes - antagonists & inhibitors JNK Mitogen-Activated Protein Kinases - metabolism K562 Cells Leukemia, T-Cell - drug therapy Leukemia, T-Cell - enzymology Leukemia, T-Cell - pathology Liver Neoplasms - drug therapy Liver Neoplasms - enzymology Liver Neoplasms - pathology Lung Neoplasms - drug therapy Lung Neoplasms - enzymology Lung Neoplasms - pathology Male Medical sciences Mice Oxadiazoles - pharmacology Oxidation-Reduction p38 Mitogen-Activated Protein Kinases - metabolism Pharmacology. Drug treatments Reactive Oxygen Species - metabolism Tumors Activity Inhibitor Enzyme Glutathione transferase Transferases Apoptosis
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
ISSN:	0008-5472 1538-7445
DOI:	10.1158/0008-5472.CAN-04-3903