Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells.

Abstract

Here we demonstrate that treatment with SAHA (suberoylanilide hydroxamic acid), a known inhibitor of histone deacetylases (HDACs), alone induced p21 and/or p27 expressions but decreased the mRNA and protein levels of Bcr-Abl, which was associated with apoptosis of Bcr-Abl-expressing K562 and LAMA-84 cells. Cotreatment with SAHA and imatinib (Gleevec) caused more down-regulation of the levels and auto-tyrosine phosphorylation of Bcr-Abl and apoptosis of these cell types, as compared with treatment with either agent alone (P <.05). This finding was also associated with a greater decline in the levels of phospho-AKT and Bcl-x(L). Significantly, treatment with SAHA also down-regulated Bcr-Abl levels and induced apoptosis of CD34(+) leukemia blast progenitor cells derived from patients who had developed progressive blast crisis (BC) of chronic myelocytic leukemia (CML) while receiving therapy with imatinib. Taken together, these findings indicate that cotreatment with SAHA enhances the cytotoxic effects of imatinib and may have activity against imatinib-refractory CML-BC.

• Authors: Ramadevi Nimmanapalli, Lianne Fuino, Corinne Stobaugh, Victoria Richon, Kapil Bhalla
• Journal: Blood (Blood) Vol. 101 Issue 8 Pg. 3236-9 (Apr 15 2003) ISSN: 0006-4971 [Print] United States
• PMID: 12446442 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Benzamides
• CDKN1A protein, human
• Cell Cycle Proteins
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins
• Enzyme Inhibitors
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Neoplasm Proteins
• Piperazines
• Pyrimidines
• Tumor Suppressor Proteins
• Cyclin-Dependent Kinase Inhibitor p27
• Vorinostat
• Imatinib Mesylate
• Fusion Proteins, bcr-abl

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Benzamides
• Blast Crisis (pathology)
• Cell Cycle Proteins (biosynthesis, genetics)
• Computer Systems
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclin-Dependent Kinase Inhibitor p27
• Cyclins (biosynthesis, genetics)
• Disease Progression
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Fusion Proteins, bcr-abl (antagonists & inhibitors)
• Gene Expression Regulation, Leukemic (drug effects)
• Histone Deacetylase Inhibitors
• Humans
• Hydroxamic Acids (pharmacology)
• Imatinib Mesylate
• K562 Cells (drug effects)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, pathology)
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis, genetics)
• Phosphorylation (drug effects)
• Piperazines (pharmacology, therapeutic use)
• Protein Processing, Post-Translational (drug effects)
• Pyrimidines (pharmacology, therapeutic use)
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured (drug effects, pathology)
• Tumor Suppressor Proteins (biosynthesis, genetics)
• Vorinostat