TY - JOUR
T1 - Downregulation of c-Myc is critical for valproic acid-induced growth arrest and myeloid differentiation of acute myeloid leukemia
AU - Cheng, Yun Chih
AU - Lin, Hsiupen
AU - Huang, Ming Jer
AU - Chow, Jyh-Ming
AU - Lin, Shufan
AU - Liu, Hsingjin-Eugene
N1 - Funding Information:
This work was supported in part by grants from Formosa Cancer Foundation and Center of Excellence for Clinical Trial and Research in Neurology Specialty (DOH-TD-B-111-002).
PY - 2007/10
Y1 - 2007/10
N2 - 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 G0/G1 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.
AB - 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 G0/G1 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.
KW - Acute myeloid leukemia
KW - Valproic acid
KW - c-Myc
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U2 - 10.1016/j.leukres.2007.03.012
DO - 10.1016/j.leukres.2007.03.012
M3 - Article
C2 - 17445886
AN - SCOPUS:34547652768
SN - 0145-2126
VL - 31
SP - 1403
EP - 1411
JO - Leukemia Research
JF - Leukemia Research
IS - 10
ER -
