Synergy between Proteasome Inhibitors and Imatinib Mesylate in Chronic Myeloid Leukemia
| Autor: | Guang-Biao Zhou, Fu-Qun Wu, Liyuan Ma, Qianli Jiang, Ting-Ting Feng, Ping Liu, Xiaoqin Chen, Xiao-Fen Pan, Zhu Chen, Zheng Hu, Ying Liu, Xiaoli Liu, Jing-Lei Liu, Sai Juan Chen, Fanyi Meng, Dapeng Liu |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
medicine.drug_class
Blotting Western lcsh:Medicine Mice Nude Antineoplastic Agents Pharmacology Piperazines Tyrosine-kinase inhibitor Mice Cell Line Tumor Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases medicine Animals Humans Protease Inhibitors Progenitor cell lcsh:Science Mice Inbred BALB C Multidisciplinary Bortezomib Chemistry lcsh:R Biochemistry/Chemical Biology of the Cell Myeloid leukemia Drug Synergism Cell Biology/Cellular Death and Stress Responses Pharmacology/Drug Interactions Pyrimidines Imatinib mesylate Hematology/Myeloproliferative Disorders including Chronic Myeloid Leukemia Apoptosis Benzamides Imatinib Mesylate Proteasome inhibitor lcsh:Q RNA Interference Proteasome Inhibitors Tyrosine kinase Research Article medicine.drug |
| Zdroj: | PLoS ONE PLoS ONE, Vol 4, Iss 7, p e6257 (2009) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0006257 |
| Popis: | BACKGROUND: Resistance developed by leukemic cells, unsatisfactory efficacy on patients with chronic myeloid leukemia (CML) at accelerated and blastic phases, and potential cardiotoxity, have been limitations for imatinib mesylate (IM) in treating CML. Whether low dose IM in combination with agents of distinct but related mechanisms could be one of the strategies to overcome these concerns warrants careful investigation. METHODS AND FINDINGS: We tested the therapeutic efficacies as well as adverse effects of low dose IM in combination with proteasome inhibitor, Bortezomib (BOR) or proteasome inhibitor I (PSI), in two CML murine models, and investigated possible mechanisms of action on CML cells. Our results demonstrated that low dose IM in combination with BOR exerted satisfactory efficacy in prolongation of life span and inhibition of tumor growth in mice, and did not cause cardiotoxicity or body weight loss. Consistently, BOR and PSI enhanced IM-induced inhibition of long-term clonogenic activity and short-term cell growth of CML stem/progenitor cells, and potentiated IM-caused inhibition of proliferation and induction of apoptosis of BCR-ABL+ cells. IM/BOR and IM/PSI inhibited Bcl-2, increased cytoplasmic cytochrome C, and activated caspases. While exerting suppressive effects on BCR-ABL, E2F1, and beta-catenin, IM/BOR and IM/PSI inhibited proteasomal degradation of protein phosphatase 2A (PP2A), leading to a re-activation of this important negative regulator of BCR-ABL. In addition, both combination therapties inhibited Bruton's tyrosine kinase via suppression of NFkappaB. CONCLUSION: These data suggest that combined use of tyrosine kinase inhibitor and proteasome inhibitor might be helpful for optimizing CML treatment. |
| Databáze: | OpenAIRE |
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