Carboxyamidotriazole-orotate inhibits the growth of imatinib-resistant chronic myeloid leukaemia cells and modulates exosomes-stimulated angiogenesis.

Abstract

The Bcr/Abl kinase has been targeted for the treatment of chronic myelogenous leukaemia (CML) by imatinib mesylate. While imatinib has been extremely effective for chronic phase CML, blast crisis CML are often resistant. New therapeutic options are therefore needed for this fatal disease. Although more common in solid tumors, increased microvessel density was also reported in chronic myelogenous leukaemia and was associated with a significant increase of angiogenic factors, suggesting that vascularity in hematologic malignancies is a controlled process and may play a role in the leukaemogenic process thus representing an alternative therapeutic target. Carboxyamidotriazole-orotate (CTO) is the orotate salt form of carboxyamidotriazole (CAI), an orally bioavailable signal transduction inhibitor that in vitro has been shown to possess antileukaemic activities. CTO, which has a reduced toxicity, increased oral bioavailability and stronger efficacy when compared to the parental compound, was tested in this study for its ability to affect imatinib-resistant CML tumor growth in a xenograft model. The active cross talk between endothelial cells and leukemic cells in the bone marrow involving exosomes plays an important role in modulating the process of neovascularization in CML. We have thus investigated the effects of CTO on exosome-stimulated angiogenesis. Our results indicate that CTO may be effective in targeting both cancer cell growth and the tumor microenvironment, thus suggesting a potential therapeutic utility for CTO in leukaemia patients.

• Authors: Chiara Corrado, Anna Maria Flugy, Simona Taverna, Stefania Raimondo, Giuliana Guggino, Rashida Karmali, Giacomo De Leo, Riccardo Alessandro
• Journal: PloS one (PLoS One) Vol. 7 Issue 8 Pg. e42310 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22879938 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• Antineoplastic Agents
• Benzamides
• Cell Adhesion Molecules
• Interleukin-8
• Piperazines
• Pyrimidines
• RNA, Messenger
• Triazoles
• Phosphotyrosine
• Orotic Acid
• carboxyamido-triazole
• Imatinib Mesylate
• Fusion Proteins, bcr-abl
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Benzamides
• Cell Adhesion (drug effects)
• Cell Adhesion Molecules (metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Exosomes (drug effects, metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Fusion Proteins, bcr-abl (metabolism)
• Gene Expression Regulation, Leukemic (drug effects)
• Human Umbilical Vein Endothelial Cells (cytology, drug effects, metabolism)
• Humans
• Imatinib Mesylate
• Interleukin-8 (metabolism)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, enzymology, pathology)
• Male
• Mice
• Neovascularization, Pathologic (drug therapy, pathology)
• Orotic Acid (analogs & derivatives, pharmacology, therapeutic use)
• Phosphorylation (drug effects)
• Phosphotyrosine (metabolism)
• Piperazines (pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrimidines (pharmacology, therapeutic use)
• RNA, Messenger (genetics, metabolism)
• Triazoles (pharmacology, therapeutic use)
• Xenograft Model Antitumor Assays