Carboxyamidotriazole inhibits cell growth of imatinib-resistant chronic myeloid leukaemia cells including T315I Bcr-Abl mutant by a redox-mediated mechanism.
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.
Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Palermo, Italy.
Chiara
C
Corrado
Stefania
S
Raimondo
Anna Maria
AM
Flugy
Simona
S
Fontana
Alessandra
A
Santoro
Giorgio
G
Stassi
Anna
A
Marfia
Flora
F
Iovino
Ralph
R
Arlinghaus
Elise C
EC
Kohn
Giacomo De
GD
Leo
Riccardo
R
Alessandro
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D051379:Mice; D009154:Mutation; D010084:Oxidation-Reduction / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D014230:Triazoles; C062058:carboxyamido-triazole; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl