Functional properties of synthetic N-acyl-L-homoserine lactone analogs of quorum-sensing gram-negative bacteria on the growth of human oral squamous carcinoma cells
Functional properties of synthetic N-acyl-L-homoserine lactone analogs of quorum-sensing gram-negative bacteria on the growth of human oral squamous carcinoma cells
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DOI：
10.1007/s10637-010-9544-x
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发表时间：
2012-02-01
影响因子：
3.4
通讯作者：
Kashiwakura, Ikuo
中科院分区：
文献类型：
--
作者：
Chai, Hongbo;Hazawa, Masaharu;Kashiwakura, Ikuo
群体传感被定义为微生物通过释放由酰基 - 共烯内酯（AHL）组成的信号分子（AHL）来感知其种群密度的能力，该分子是一种自动诱导剂（AI）。先前的结构活性关系（SAR）研究表明，3-氧基组，L形式的同甲烯内酯和长酰基侧链在凋亡诱导中具有至关重要的作用。制备了各种类型的铜绿假单胞菌的合成AI类似物，并进行了SAR研究，以确定其对源自牙龈癌CA9-22细胞和舌癌癌症SAS细胞的人口服鳞状癌细胞的作用。不仅检查了抗增殖电位，而且还检查了针对这些细胞的辐射敏化作用。发现抗增生活性部分取决于HSL结构和酰基侧链长度。此外，几种化合物5和87化合物对CA9-22和SAS细胞均显示出抗增殖作用，还诱导了对CA9-22细胞的辐射敏感性。单独的化合物5诱导凋亡细胞死亡，伴随着细胞周期和caspase-3激活中亚G1相的积累，化合物5的辐射敏化作用可归因于增强的凋亡诱导。相反，单独或组合使用化合物87处理的CA9-22中的细胞周期分布没有显着改变。但是，这两种化合物都缺乏3氧，其酰基侧链的长度不一定很长。这项SAR研究表明，缺乏凋亡诱导的推荐特征的HSL类似物清楚地表明，CA9-22细胞中的抗增殖和辐射敏感性。
Quorum sensing is defined as the ability of microorganisms to sense their population density via the release of signaling molecules composed of acyl-homoserine lactone (AHL), which is a type of autoinducer (AI). Previous structure-activity relationship (SAR) studies demonstrated that the 3-oxo group, homoserine lactone of L-form, and long acyl side chain have crucial roles in apoptosis induction. Various types of synthetic AI analogs of Pseudomonas aeruginosa were prepared, and SAR study was conducted to determine their effects against human oral squamous carcinoma cells derived from gingival carcinoma Ca9-22 cells and tongue cancer SAS cells. Not only the antiproliferative potential but also the radiation-sensitizing effects against these cells were examined. It was found that antiproliferative activity partly depended on HSL structure and acyl side chain length. Moreover, a few compounds, compound 5 and 87, showed antiproliferative effects against both Ca9-22 and SAS cells, and also induced radiation-sensitizing effects against Ca9-22 cells. Compound 5 alone induced apoptotic cell death accompanied by sub-G1 phase accumulation in cell cycle and caspase-3 activation, and radiation-sensitizing effects of compound 5 could be attributed to enhanced apoptosis induction. In contrast, there were no remarkable alterations in cell cycle distribution in Ca9-22 treated with compound 87 alone or in combination. However, both compounds lack 3-oxo and their acyl side chain lengths are not necessarily long. This SAR study demonstrated that HSL analogs, which lacked the recommended characteristics for apoptosis induction clearly showed antiproliferative and radiation-sensitizing activity in Ca9-22 cells.