Antileukemia activity of the combination of 5-aza-2'-deoxycytidine with valproic acid.
Aberrant DNA methylation of promoter associated CpG islands is a common phenomenon in human leukemias and cooperates with histone code changes in the control of gene expression. 5-Aza-2'-deoxycytidine (DAC) is a hypomethylating agent with significant antileukemia activity in humans. Recently, valproic acid (VPA) has been shown to be a histone deacetylase inhibitor and to have potential antineoplastic activity. In this report, we study the in vitro effects of the combination of DAC and VPA on the leukemic cell lines HL-60 and MOLT4. DAC alone induced growth inhibition and apoptosis at doses of 1 microM, an effect observed with VPA at doses of 1 mM. Each drug alone had the capacity to induce the expression of p57KIP2 and p21CIP1. DAC mediated hypomethylation of p57KIP2 was not required to induce p57KIP2 gene expression, and treatment with DAC resulted in the induction of p21CIP1. VPA induced global histone acetylation, an effect enhanced by the addition of DAC. The combination of DAC and VPA had a synergistic effect in terms of growth inhibition, induction of apoptosis and reactivation of p57KIP2 and p21CIP1. These results suggest that the combination of DAC and VPA could have significant antileukemia activity in vivo.
Yang
Hui
H
Department of Leukemia, University of Texas, MD Anderson Cancer Center, Box 428, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Hoshino
Koyu
K
Sanchez-Gonzalez
Blanca
B
Kantarjian
Hagop
H
Garcia-Manero
Guillermo
G
D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000633:toxicity*; D045744:Cell Line, Tumor; D017931:DNA Primers; D000077209:Decitabine; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018922:HL-60 Cells / Q000187:drug effects*; D006801:Humans; D015458:Leukemia, T-Cell; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014635:Valproic Acid / Q000633:toxicity*
D000903:Antibiotics, Antineoplastic; D017931:DNA Primers; D014635:Valproic Acid; D000077209:Decitabine; D001374:Azacitidine