[Inhibitory effect on proliferation of KG1a cell line by methyltransferase inhibitors].
To explore the possibility of a new therapeutic strategy for leukemia by intervening in the DNA methylation to re-express p15 suppressor gene, methylation inhibitors, 5-Aza-2'-deoxycytidine (5-Aza-CdR) and cell differentiation agent (CDAII) were used to treat myelogenous leukemia cell line KG1a in which p15 gene expression was suppressed due to DNA hypermethylation. The biological characteristics of KG1a cells untreated or treated with the agents were investigated and analyzed using morphology, methylation specific-PCR (MSP), (3)H-labeled microassay technique, restriction endonuclease reaction, flow cytometry and immunofluorescence methods. The results indicated that both agents showed concentration-dependent and time-dependent inhibition of cell proliferation. 5-Aza-CdR and CDAII induced apoptosis and cell differentiation with G(2) and G(0)/G(1) arrest respectively. Furthermore, DNA methyltransferase activity and level of methylation in genomic DNA were decreased and p15 protein was re-expressed partially. It is concluded that it is possible to treat leukemia by intervening in the DNA methylation using methyltransferase inhibitors and it is worth to make a thorough study on mechanism of the new strategy.
Chen
Hua
H
Department of Hematology, The First Hospital of Peking University, Beijing 100034, China.
Wu
Shu-Lan
SL
Zhu
Qiang
Q
Shi
Yong-Jin
YJ
Xu
Guo-Bin
GB
Wang
Jian-Zhong
JZ
D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division; D002460:Cell Line; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016147:Genes, Tumor Suppressor; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology; D025521:Tumor Suppressor Proteins
C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D025521:Tumor Suppressor Proteins; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine