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Proapoptotic Activity of New Glutathione S-Transferase Inhibitors

Departments of ¹ Chemical Sciences and Technologies and ² Biology, University of Rome "Tor Vergata"; ³ Department of Drug Research and Evaluation, Section of Pharmacogenetics, Drug Resistance and Experimental Therapeutics, Istituto Superiore di Sanità; and ⁴ Children's Hospital IRCCS "Bambin Gesù," Rome, Italy

Requests for reprints: Anna Maria Caccuri, Department of Chemical Sciences and Technologies, University of Rome "Tor Vergata", Viale della Ricerca Scientifica, 00133-Rome, Italy. Phone: 39-06-72594378; Fax: 39-06-72594328; E-mail: caccuri{at}uniroma2.it.

Selected 7-nitro-2,1,3-benzoxadiazole derivatives have been recently found very efficient inhibitors of glutathione S-transferase (GST) P1-1,⁵ 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 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 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.

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