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

Ramadevi Nimmanapalli, Lianne Fuino, Purva Bali, Maura Gasparetto, Michele Glozak, Jianguo Tao, Lynn Moscinski, Clayton Smith, Jie Wu, Richard Jove, Peter Atadja, Kapil Bhalla

Research output: Contribution to journalArticle

244 Scopus citations

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 of -refractory human leukemia.

Original languageEnglish (US)
Pages (from-to)5126-5135
Number of pages10
JournalCancer research
Volume63
Issue number16
StatePublished - Aug 15 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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