Galloyl cyclic-imide derivative CH1104I inhibits tumor invasion through suppressing matrix metalloproteinase activity
Galloyl cyclic-imide derivative CH1104I inhibits tumor invasion through suppressing matrix metalloproteinase activity
复制标题
没食子酰环酰亚胺衍生物 CH1104I 通过抑制基质金属蛋白酶活性抑制肿瘤侵袭
DOI：
10.1097/cad.0b013e328313e15b
复制
发表时间：
2008-11-01
影响因子：
2.3
通讯作者：
Qu, Xian-Jun
中科院分区：
文献类型：
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作者：
Chen, Ming-Hui;Cui, Shu-Xiang;Qu, Xian-Jun
基质金属蛋白酶(MMP2)和MMP9被认为与肿瘤细胞的转移能力有关，因为它们能够降解基底膜的主要成分IV型胶原，并在恶性肿瘤中高表达。(S)-甲基6-(benzyloxycarbonylamino)-2-(2-((S)-2，6-dioxo-3-(3，4，5-trimethoxybenzamido)-1-乙酰氨基己酸甲酯(CH1104I)是一种没食子酸环-亚胺衍生物，专为适合和延伸到基质金属蛋白酶-2和基质金属蛋白酶-9的S1‘活性口袋而设计。我们的目的是评价CH1104I作为抗肿瘤细胞侵袭和转移候选化合物的有效性。CH1104I显著抑制明胶酶的活性，琥珀酸化明胶的降解率降低。明胶酶谱分析表明，化合物(7-210Mol/L)抑制人卵巢癌 μ细胞产生MMP2和MMP9的活性。免疫细胞化学染色和Western印迹分析观察对基质金属蛋白酶-2和基质金属蛋白酶-9表达的抑制作用。结果表明，CH1104I抑制酵母菌的表达，抑制活性的基质金属蛋白酶-2和基质金属蛋白酶-9的表达。检测CH1104I对SKOV3细胞侵袭和迁移的影响。穿孔运动实验和划痕实验均表明CH1104I对SKOV3细胞具有较强的抗侵袭和抗迁移作用。此外，还利用Lewis肺癌模型对CH1104I的体内疗效进行了评价。CH1104I(25-100 mg/kg)对小鼠肺转移有明显的抑制作用。这些结果提示CH1104I是一种潜在的基质金属蛋白酶-2和基质金属蛋白酶-9的抑制剂，可能有效地抑制肿瘤的侵袭和转移。
Matrix metalloproteinase (MMP)-2 and MMP-9 have been associated with the ability of tumor cells to metastasize because of their capacity to degrade type IV collagen, the main component of basement membrane, and to their elevated expression in malignant tumors. (S)-methyl 6-(benzyloxycarbonylamino)-2-(2-((S)-2,6-dioxo-3-(3,4,5-trimethoxybenzamido) piperidin-1-yl) acetamido) hexanoate (CH1104I) is a galloyl cyclic-imide derivative designed to fit and extend into the S1′ active pocket of MMP-2 and MMP-9. We aimed to evaluate the efficacy of CH1104I as a candidate compound for antiinvasion and antimetastasis of tumor cells. CH1104I significantly blocked gelatinase activity as evidenced by a decrease in the degradation of succinylated gelatin. Gelatin zymography analysis showed that the compound (7–210 μmol/l) inhibited the activity of MMP-2 and MMP-9 produced by human ovarian carcinoma SKOV3 cells. Inhibition of MMP-2 and MMP-9 expression was also observed using the assays of immunocytochemical staining and western blot analysis. The results showed that CH1104I suppressed the expression of zymogens and active MMP-2 and MMP-9. The effects of CH1104I on the invasion and migration of SKOV3 cells were then measured. Both the trans-well motility assay and wound scratch assay indicated that CH1104I was very effective for the antiinvasion and antimigration of SKOV3 cells. Furthermore, the Lewis lung carcinoma model was used to evaluate the efficacy of CH1104I in vivo. A significant inhibition of pulmonary metastasis of carcinoma cells was observed in CH1104I-administrated mice (25–100 mg/kg). These results suggest that CH1104I is a potential MMP-2 and MMP-9 inhibitor that may effectively suppress tumor invasion and metastasis.