Effects of carboxyamidotriazole on in vitro models of imatinib-resistant chronic myeloid leukemia.

6533b826fe1ef96bd1283d44

RESEARCH PRODUCT

Effects of carboxyamidotriazole on in vitro models of imatinib-resistant chronic myeloid leukemia.

Giordano M Paolo Colomba A. Flugy Simona Fontana Riccardo Alessandro Elise C. Kohn Alessandra Santoro Giacomo De Leo Chiara Corrado

subject

Physiology MAP Kinase Signaling System Clinical Biochemistry Fusion Proteins bcr-abl Down-Regulation Apoptosis Signal transduction inhibitor Pharmacology Piperazines chemistry.chemical_compound hemic and lymphatic diseases Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive medicine Humans Enzyme Inhibitors Phosphotyrosine CML neoplasms In Situ Hybridization Fluorescence Chronic Myelogenous Leukemia Cell Proliferation Carboxyamidotriazole business.industry CAI Myeloid leukemia Imatinib Cell Biology Triazoles medicine.disease CRKL Enzyme Activation Gene Expression Regulation Neoplastic Leukemia Imatinib mesylate Pyrimidines chemistry Drug Resistance Neoplasm Molecular Probes Benzamides imatinib resistance Imatinib Mesylate ras Proteins CML; imatinib resistance; CAI Carboxyamidotriazole business signal transduction Chronic myelogenous leukemia medicine.drug

description

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.

year	journal	country	edition	language
2008-01-01	Journal of cellular physiology

10.1002/jcp.21290 https://pubmed.ncbi.nlm.nih.gov/17924401