Peroxisome proliferator-activated receptor gamma as a novel target in cancer therapy: binding and activation by an aromatic fatty acid with clinical antitumor activity.
Peroxisome proliferator-activated receptor gamma as a novel target in cancer therapy: binding and activation by an aromatic fatty acid with clinical antitumor activity.
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发表时间：
2000-03
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通讯作者：
Dvorit Samid;Michelle Wells;M. Greene;Weiyin Shen;Colin N. A. Palmer;Alain Thibault
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作者：
Dvorit Samid;Michelle Wells;M. Greene;Weiyin Shen;Colin N. A. Palmer;Alain Thibault
芳香族脂肪酸是一类低毒药物，在实验模型和人体中都显示出抗肿瘤活性，苯乙酸酯就是其中的一个原型。通过体外模型，我们发现苯乙酸酯抑制肿瘤生长与核受体超家族成员过氧化物酶体增殖物激活受体γ (PPARgamma)的激活密切相关。支持以下观察结果：(a)使用已建立的肿瘤系和强迫表达模型证明，苯乙酸酯作为细胞抑制剂的功效与治疗前的PPARgamma水平相关；(b)在应答性肿瘤细胞中，PPARgamma表达在治疗后2-9小时内上调，随后p21waf1（细胞周期阻滞的标志）表达增加；(c)抑制丝裂原活化蛋白激酶（PPARgamma的负调节因子），增强药物活性；(d)苯乙酸酯直接与PPARgamma的配体结合位点相互作用，激活其转录功能。结合和激活PPARgamma的能力是苯乙酸酯的生物活性类似物所共有的，并且与它们作为抗肿瘤药物的效力相对应（苯乙酸酯<苯丁酸酯<对氯苯乙酸酯<对碘苯丁酸酯），而非活性衍生物苯乙酰谷氨酰胺对PPARgamma没有影响。这些发现表明PPARgamma是癌症治疗的新靶点，并首次鉴定出具有选择性抗肿瘤活性的配体。
Aromatic fatty acids, of which phenylacetate is a prototype, constitute a class of low toxicity drugs with demonstrated antitumor activity in experimental models and in humans. Using in vitro models, we show here a tight correlation between tumor growth arrest by phenylacetate and activation of peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily. In support are the following observations: (a) the efficacy of phenylacetate as a cytostatic agent was correlated with pre-treatment levels of PPARgamma, as documented using established tumor lines and forced expression models; (b) in responsive tumor cells, PPARgamma expression was up-regulated within 2-9 h of treatment preceding increases in p21waf1, a marker of cell cycle arrest; (c) inhibition of mitogen-activated protein kinase, a negative regulator of PPARgamma, enhanced drug activity; and (d) phenylacetate interacted directly with the ligand-binding site of PPARgamma and activated its transcriptional function. The ability to bind and activate PPARgamma was common to biologically active analogues of phenylacetate and corresponded to their potency as antitumor agents (phenylacetate < phenylbutyrate < p-chloro-phenylacetate < p-iodo-phenylbutyrate), whereas an inactive derivative, phenylacetylglutamine, had no effect on PPARgamma. These findings point to PPARgamma as a novel target in cancer therapy and provide the first identification of ligands that have selective antitumor activity in patients.