Effects of carboxyamidotriazole on in vitro models of imatinib-resistant chronic myeloid leukemia.
Although imatinib mesylate (IM) has revolutionized the treatment of chronic myeloid leukemia (CML), some patients develop resistance with progression of leukemia. Alternative or additional targeting of signaling pathways deregulated in bcr-abl-driven CML cells may provide a feasible option for improving clinical response and overcoming resistance. In this study, we show that carboxyamidotriazole (CAI), an orally bioavailable calcium influx and signal transduction inhibitor, is equally effective in inhibiting the proliferation and bcr-abl dependent- and independent-signaling pathways in imatinib-resistant CML cells. CAI inhibits phosphorylation of cellular proteins including STAT5 and CrkL at concentrations that induce apoptosis in IM-resistant CML cells. The combination of imatinib and CAI also down-regulated bcr-abl protein levels. Since CAI is already available for clinical use, these results suggest that it may be an effective addition to the armamentarium of drugs for the treatment of CML.
Alessandro
Riccardo
R
Dipartimento di Biopatologia e Metodologie Biomediche, Sezione di Biologia e Genetica, Università di Palermo, Italy. ricale@unipa.it
Fontana
Simona
S
Giordano
Margherita
M
Corrado
Chiara
C
Colomba
Paolo
P
Flugy
Anna Maria
AM
Santoro
Alessandra
A
Kohn
Elise C
EC
De Leo
Giacomo
G
D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate; D017404:In Situ Hybridization, Fluorescence; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D015335:Molecular Probes / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D018631:ras Proteins / Q000378:metabolism
D001549:Benzamides; D004791:Enzyme Inhibitors; D015335:Molecular Probes; D010879:Piperazines; D011743:Pyrimidines; D014230:Triazoles; D019000:Phosphotyrosine; C062058:carboxyamido-triazole; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D018631:ras Proteins