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Studies on the regulation of cell cycle by allyl sulfides and their anticancer properties.

烯丙基硫醚对细胞周期的调节及其抗癌特性的研究。

基本信息

批准号：
15380097
负责人：
ARIGA Toyohiko
金额：
$ 9.02万
依托单位：
Nihon University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15380097/
关键词：
diallyl trisulfide colon cancer apoptosis tubulin cell cycle garlic allyl sulfide LC-MS MS cancer cancer cell histone deacetylase

项目摘要

Allyl sulfides are characteristic flavor components obtained from garlic. These sulfides are thought to be responsible for their epidemiologically proven anticancer effect on garlic eaters. This study was aimed at clarifying the molecular basis of this anticancer effect of garlic by using human colon cancer cell lines HCT-15 and DLD-1. The growth of the cells was significantly suppressed by diallyl trisulfide (DATS, HCT-15 IC_<50>=11.5 μM, DLD-1 IC_<50>=13.3 μM) ; however, neither diallyl monosulfide (DAS) nor diallyl disulfide (DADS) showed such effect. The proportion of HCT-15 and that of DLD-1 cells residing at G1 and S phases were decreased by DATS, and their population at the G2/M phase was markedly increased for up to 12h. The cells with a sub-G1 DNA content were increased thereafter. Caspase-3 activity was also dramatically increased by DATS. FACS analysis performed on the cells arrested at the G1/S boundary revealed cell cycle-dependent induction of apoptosis through the transition of G2/M to G1 phase by DATS. DATS inhibited tubulin polymerization in an in vitro cell-free system. DATS disrupted microtubule network formation of the cells and microtubule fragments could be seen at the interphase. Peptide mass mapping by LC-MS/MS analysis for DATS-treated tubulin demonstrated that there was a specific oxidative modification of cysteine residues Cys12β and Cys354β to form S-allylmercaptocysteine with a peptide mass increase of 72.1 Da. The potent antitumor activity of DATS was also demonstrated in the nude mice bearing HCT-15 xenografts. This is a first paper describing about intracellular target molecules directly modified by garlic components.

烯丙基硫化物是从大蒜中提取的特有风味成分。这些硫化物被认为是流行病学证明对大蒜食用者具有抗癌作用的原因。本研究以人结肠癌细胞株HCT-15和DLD-1为研究对象，旨在阐明大蒜这种抗癌作用的分子基础。二烯丙基三硫化物(DATS，Hct-15IC_&lt；50&gt；=11.5μM，DLD-1IC_&lt；50&gt；=13.3μM)对细胞生长有明显的抑制作用，而二烯丙基单硫醚(DAS)和二烯丙基二硫(DADS)均无此作用。DATS可降低Hct-15和DLD-1细胞停留在G1期和S期的比例，并使其G2/M期细胞数显著增加至12h。DNA含量为亚G1期的细胞数随后增加。DATS还显著提高了caspase-3的活性。对滞留在G1/S交界处的细胞进行的流式细胞仪分析表明，DATS通过G2/M期向G1期的转变诱导细胞周期依赖性的凋亡。DATS在体外无细胞体系中抑制微管蛋白聚合。DATS破坏了细胞的微管网络形成，在间期可见微管碎片。经DATS处理的微管蛋白的LC-MS/MS分析表明，半胱氨酸残基Cys12β和Cys354β发生了特异性的氧化修饰，形成了S-烯丙基硫代半胱氨酸，其多肽质量增加了72.1Da。DATS在荷瘤裸鼠体内也显示出较强的抗肿瘤活性。这是第一篇关于大蒜成分直接修饰细胞内靶分子的论文。