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学科主题: 药学
题名:
Two newly synthesized 5-methyltetrahydrofolate-like compounds inhibit methionine synthase activity accompanied by cell cycle arrest in G(1)/S phase and apoptosis in vitro
作者: Tang, Cai1; Zhang, Zhili2; Xu, Bo1; Li, Min1; Liu, Junyi2; Cui, Jingrong1
关键词: 5-methyltetrahydrofolate ; anticancer ; apoptosis ; cell cycle ; HL-60 ; methionine synthase
刊名: ANTI-CANCER DRUGS
发表日期: 2008-08-01
卷: 19, 期:7, 页:697-704
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Oncology ; Pharmacology & Pharmacy
研究领域[WOS]: Oncology ; Pharmacology & Pharmacy
关键词[WOS]: ISOLATED RAT HEPATOCYTES ; NITROUS-OXIDE ; FOLATE-DEFICIENCY ; LEUKEMIA-CELLS ; NITRIC-OXIDE ; CANCER-CELLS ; COBALAMIN ; INACTIVATION ; PATHWAY ; PROLIFERATION
英文摘要:

Cobalamin-dependent methionine synthase, with a cofactor of vitamin B12, catalyzes the reaction of 5-methyltetrahydrofolate and homocysteine to form methionine and tetrahydrofolate, which takes a core position in folate cycle, one-carbon-unit transfer, and sulfur amino acid pathways. The ′methyl folate trap′ hypothesis suggests that methionine synthase is a potential target for anticancer drug development. ZL031 and ZL033 are 5-methyltetrahydrofolate-like compounds that have been newly synthesized as potential inhibitors of the enzyme. To identify the effect of these two compounds on methionine synthase activity, a spectrophotometric assay was used and the results proved that ZL031 and ZL033 inactivated methionine synthase in HL-60 cells with an IC50 dose of 10.0 and 1.4 mu mol/l, respectively. Moreover, obvious inhibitory effect on proliferation of HL-60 cells was observed, leading to our further investigation of the underlying anticancer mechanism. Under the circumstances of methionine synthase deficiency and subsequent folate depletion, cell cycle was arrested in G1/S phase and apoptosis was also observed. Analysis of cell cycle regulatory proteins demonstrated that cyclin E and cyclin-dependent kinase 2 were both increased. Furthermore, reduction of caspase-3, poly (ADP-ribose) polymerase, caspase-8, and caspase-9 protein levels were observed. In all the biological experiments we have performed, ZL033 has shown a better efficacy compared with ZL031. These results suggest that ZL031 and ZL033, as novel methionine synthase inhibitors, caused G1/S phase delay and apoptosis and eventually inhibit the proliferation of HL-60 cells in vitro. ZL033, with a carboxylic acid substituent, might have a better potential for drug development than ZL031 with an ester substituent.

语种: 英语
WOS记录号: WOS:000257788400005
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/64890
Appears in Collections:北京大学药学院_化学生物学系_期刊论文

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作者单位: 1.Peking Univ, Hlth Sci Ctr, State Key Lab Nat & Biomimet Drugs, Beijing 100083, Peoples R China
2.Peking Univ, Hlth Sci Ctr, Sch Pharmaceut Sci, Dept Biol Chem, Beijing 100083, Peoples R China

Recommended Citation:
Tang, Cai,Zhang, Zhili,Xu, Bo,et al. Two newly synthesized 5-methyltetrahydrofolate-like compounds inhibit methionine synthase activity accompanied by cell cycle arrest in G(1)/S phase and apoptosis in vitro[J]. ANTI-CANCER DRUGS,2008,19(7):697-704.
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