PloS one, 2012-08, Vol.7 (8), p.e42310
2012
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- Autor(en) / Beteiligte
- Titel
- Carboxyamidotriazole-orotate inhibits the growth of imatinib-resistant chronic myeloid leukaemia cells and modulates exosomes-stimulated angiogenesis
- Ist Teil von
- PloS one, 2012-08, Vol.7 (8), p.e42310
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2012
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0042310Titel-ID: cdi_plos_journals_1326223048
- Format
- –
- Schlagworte
- Abl gene, Angiogenesis, Animals, Antineoplastic Agents - pharmacology, Antineoplastic Agents - therapeutic use, BCR gene, BCR protein, Benzamides, Bioavailability, Biology, Biology and Life Sciences, Blast crisis, Blast resistance, Bone marrow, Cancer, Cell Adhesion - drug effects, Cell Adhesion Molecules - metabolism, Cell Biology, Cell Line, Tumor, Cell Movement - drug effects, Cell Proliferation - drug effects, Cellular signal transduction, Chronic myeloid leukemia, Crosstalk, Drug Resistance, Neoplasm - drug effects, Drug Resistance, Neoplasm - genetics, Endothelial cells, Exosomes, Exosomes - drug effects, Exosomes - metabolism, Experiments, Extracellular Signal-Regulated MAP Kinases - metabolism, Fusion Proteins, bcr-abl - metabolism, Gene Expression Regulation, Leukemic - drug effects, Growth, Health aspects, Human Umbilical Vein Endothelial Cells - cytology, Human Umbilical Vein Endothelial Cells - drug effects, Human Umbilical Vein Endothelial Cells - metabolism, Humans, Imatinib, Imatinib Mesylate, Interleukin-8 - metabolism, Kinases, Leukemia, Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology, Lung cancer, Male, Medicine, Medicine and Health Sciences, Mice, Mutation, Neovascularization, Neovascularization, Pathologic - drug therapy, Neovascularization, Pathologic - pathology, Oncology, Orotic Acid - analogs & derivatives, Orotic Acid - pharmacology, Orotic Acid - therapeutic use, Phosphorylation, Phosphorylation - drug effects, Phosphotyrosine - metabolism, Piperazines - pharmacology, Piperazines - therapeutic use, Proto-Oncogene Proteins c-akt - metabolism, Pyrimidines - pharmacology, Pyrimidines - therapeutic use, RNA, Messenger - genetics, RNA, Messenger - metabolism, Salts, Signal transduction, Solid tumors, Therapeutic applications, Toxicity, Triazoles - pharmacology, Triazoles - therapeutic use, Tumors, Vascularization, Xenograft Model Antitumor Assays, Xenografts, Xenotransplantation