Insights into the mevalonate pathway in the anticancer effect of a platinum complex on human gastric cancer cells
Insights into the mevalonate pathway in the anticancer effect of a platinum complex on human gastric cancer cells
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铂络合物对人胃癌细胞抗癌作用中甲羟戊酸途径的见解
DOI：
10.1016/j.ejphar.2017.06.035
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发表时间：
2017-09-05
影响因子：
5
通讯作者：
Lin, Jianguo
中科院分区：
文献类型：
--
作者：
Qiu, Ling;Yang, Hui;Lin, Jianguo
为了寻找高效、低副作用的新型抗癌药物，设计合成了一种铂（II）配合物[Pt（en）]（2）ZL [en =乙二胺; ZL = 1-羟基-3-（1H-咪唑-1-基）乙烷-1，1-二基双膦酸，俗称唑来膦酸]。它对人癌细胞SGC 7901、HepG 2、MCF-7、MDA-MB-231、HCT 116和U2 OS显示出细胞毒作用，并且对SGC 7901的细胞毒作用特别显著。与相应的配体ZL相比，它对胃癌细胞SGC 7901和肝癌细胞HepG 2的抑制作用更强，而对正常细胞GES-1和LO 2的抑制作用更弱。为探讨甲羟戊酸途径在[Pt（en）]（2）ZL抗肿瘤作用机制中的作用，系统研究了甲羟戊酸途径重要中间体法呢基焦磷酸（FPP）和香叶基香叶基焦磷酸（GGPP）的前体法尼醇（FOH）和香叶基香叶醇（GGOH）对[Pt（en）]（2）ZL抗人胃癌细胞SGC 7901细胞毒作用的影响。因为抑制甲羟戊酸途径中的关键酶法尼基焦磷酸合酶（FPPS）被认为是配体ZL的大多数抗癌作用的机制。实验结果表明，FOH和GGOH都能拯救胃癌细胞，尤其是FOH。[Pt（en）]（2）ZL诱导的细胞周期阻滞和凋亡可被FOH和小鸟嘌呤核苷酸结合调节蛋白的异戊烯化所抑制[Pt（en）]（2）ZL通过抑制甲羟戊酸途径发挥抗肿瘤作用。这将为[Pt（en）]（2）ZL的作用机制提供深入的见解。
A platinum(II) complex [Pt(en)](2)ZL [en = ethylenediamine; ZL = 1-hydroxy-3(1H-imidazol-1-yl)ethane-1,1-diylbisphosphonic acid, commonly called as zoledronic acid] has been designed and synthesized recently in order to look for new anticancer drugs with high efficacy and low side effects. It exhibited cytotoxic effects on the human cancer cells SGC7901, HepG2, MCF-7, MDA-MB-231, HCT116, and U2OS, and the cytotoxicity against SGC7901 is particularly remarkable. It also showed higher cytotoxicity and better selectivity than the corresponding ligand ZL in inhibiting cancer cells SGC7901 and HepG2 rather than normal cells GES-1 and LO2. To investigate the role of mevalonate pathway involved in the mechanism of anticancer action of [Pt(en)](2)ZL, the effects of farnesol (FOH) and geranylgeraniol (GGOH), precursors of important mevalonate pathway intermediates farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), on the cytotoxic effects of [Pt(en)](2)ZL against the human gastric cancer cells SGC7901 were investigated systematically, since inhibition of the key enzyme farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway was acknowledged as the mechanism of most anticancer actions of the ligand ZL. The experiments revealed that FOH and GGOH both rescued the SGC7901 cells, especially FOH. The cell cycle arrest and apoptosis of SGC7901 cells induced by [Pt(en)](2)ZL was decreased by the addition of FOH, and the prenylation of small guanine -nucleotide -binding regulatory proteins (small G proteins) down-regulated by [Pt(en)](2)ZL was recovered by the addition of FOH, demonstrating that [Pt(en)](2)ZL exerted anticancer effects on SGC7901 via inhibiting the mevalonate pathway. This will provide deep insights into the mechanism of action of [Pt(en)](2)ZL.