Carboxyamidotriazole inhibits cell growth of imatinib-resistant chronic myeloid leukaemia cells including T315I Bcr-Abl mutant by a redox-mediated mechanism.

Chiara Corrado, Stefania Raimondo, Anna Maria Flugy, Simona Fontana, Alessandra Santoro, Giorgio Stassi, Anna Marfia, Flora Iovino, Ralph Arlinghaus, Elise C Kohn, Giacomo De Leo, Riccardo Alessandro

Index: Cancer Lett. 300(2) , 205-14, (2011)

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Abstract

Mutation of the Bcr-Abl oncoprotein is one of most frequent mechanisms by which chronic myelogenous leukemia (CML) cells become resistant to imatinib. Here, we show that treatment of cell lines harbouring wild type or mutant BCR-ABL with carboxyamidotriazole (CAI), a calcium influx and signal transduction inhibitor, inhibits cell growth, the expression of Bcr-Abl and its downstream signalling, and induces apoptosis. Moreover, we show that CAI acts by increasing intracellular ROS. Clinically significant, CAI has also inhibitory effects on T315I Bcr-Abl mutant, a mutation that causes CML cells to become insensitive to imatinib and second generation abl kinase inhibitors.Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.