Histone deacetylase inhibitor LAQ824 both lowers expression and promotes proteasomal degradation of Bcr-Abl and induces apoptosis of imatinib mesylate-sensitive or -refractory chronic myelogenous leukemia-blast crisis cells.
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| Abstract |
Treatment with LAQ824 (Novartis Pharmaceutical, Inc.), a cinnamyl hydroxamic acid analogue inhibitor of histone deacetylases, depleted the mRNA and protein expression of Bcr-Abl in human chronic myeloid leukemia blast crisis (CML-BC) cells. Exposure to LAQ824 induced the expression of the cell cycle-dependent kinase inhibitors p21 and p27 and caused cell cycle G(1)-phase accumulation and apoptosis of CML-BC cells. LAQ824 also induced acetylation of heat shock protein 90. This inhibited the chaperone association of Bcr-Abl with heat shock protein 90, thereby promoting the proteasomal degradation of Bcr-Abl. Cotreatment with LAQ824 increased imatinib mesylate-induced apoptosis of CML-BC cells. Additionally, LAQ824 down-regulated the levels of mutant Bcr-Abl possessing the T315I point mutation, as well as induced apoptosis of imatinib-refractory primary CML-BC cells. Therefore, LAQ824 may be a promising therapeutic agent in the treatment of imatinib-sensitive or -refractory human leukemia.
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| Authors | Ramadevi Nimmanapalli, Lianne Fuino, Purva Bali, Maura Gasparetto, Michele Glozak, Jianguo Tao, Lynn Moscinski, Clayton Smith, Jie Wu, Richard Jove, Peter Atadja, Kapil Bhalla |
| Journal | Cancer research (Cancer Res) Vol. 63 Issue 16 Pg. 5126-35 (Aug 15 2003) ISSN: 0008-5472 [Print] United States |
| PMID | 12941844 (Publication Type: Journal Article) |
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