Downregulation of c-Myc is critical for valproic acid-induced growth arrest and myeloid differentiation of acute myeloid leukemia.
Valproic acid (VPA), an agent used for neurological disorders, has been shown to be a novel class of histone deacetylase inhibitor (HDACI), able to induce apoptosis and myeloid differentiation of acute myeloid leukemia (AML). In this study, we examined the underlying mechanisms in VPA-mediated activities in AML cells. VPA not only inhibited the growth of HL-60, U937 and NB4 cells by causing cell-cycle arrest at G(0)/G(1) phase and apoptosis, but also induced morphologic and phenotypic changes. VPA markedly increased p21WAF1, and downregulated c-Myc expression at transcriptional levels. Ectopic expression of wildtype c-Myc and T58A mutant significantly inhibited VPA-mediated growth inhibition. As with results from cell line studies, VPA also downregulated c-Myc levels, and induced apoptosis and myeloid differentiation of primary AML cells, leading to decreased colony-forming ability. Given the role of c-Myc in leukemogenesis, our study suggests that VPA might be a potential therapeutic agent for AML.
Cheng
Yun-Chih
YC
Department of Internal Medicine, Wanfang Hospital-Taipei Medical University, Taipei, Taiwan.
Lin
Hsiupen
H
Huang
Ming-Jer
MJ
Chow
Jyh-Ming
JM
Lin
Shufan
S
Liu
H Eugene
HE
D000208:Acute Disease; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014635:Valproic Acid / Q000494:pharmacology*
D000970:Antineoplastic Agents; D014635:Valproic Acid