Structure-dependent activity of glycyrrhetinic acid derivatives as peroxisorne proliferator-activated receptor γ agonists in colon cancer cells
Structure-dependent activity of glycyrrhetinic acid derivatives as peroxisorne proliferator-activated receptor γ agonists in colon cancer cells
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DOI：
10.1158/1535-7163.mct-07-0022
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发表时间：
2007-05-01
影响因子：
5.7
通讯作者：
Safe, Stephen
中科院分区：
文献类型：
--
作者：
Chintharlapalli, Sudhakar;Papineni, Sabitha;Safe, Stephen
甘草甜素是甘草中主要的植物化学成分，是一种五环三萜苷。该化合物及其水解产物甘草次酸与甘草提取物的多种治疗特性有关。我们研究了2-氰基取代的大黄酸类似物对它们的细胞毒性和作为选择性过氧化物酶体激活受体γ（PPAR γ）激动剂的活性的影响。2-氰基-3，11-二氧代-18 β-生育酚-1，12-二烯-30-酸甲酯（β-CDODA-Me）和甲基2-氰基-3，11-二氧代-18 α-β-l，12-二烯-30-酸酯（α-CDODA-Me）比它们的去氰基类似物对结肠癌细胞更具细胞毒性，并且将2-氰基引入到五环系统中对于α-CDODA-Me的PPAR γ激动剂活性是必需的。Me和β-CDODA-Me异构体。然而，在哺乳动物双杂交试验中，这两种化合物差异诱导的相互作用的PPAR γ与coactivators，这表明这些异构体，不同的立体化学仅在C18的影响构象的E-环，是选择性受体调节剂。结肠癌细胞中的这种选择性表现为诱导两种促凋亡蛋白，即小窝蛋白-1和肿瘤抑制基因Kruppel样因子-4（KLF-4）。β-CDODA-Me而不是α-CDODA-Me诱导SW 480结肠癌细胞中的小窝蛋白-1，而HT-29和HCT-15结肠癌细胞中的小窝蛋白-1被两种化合物诱导。CDODA-Me异构体诱导HT-29和SW 480细胞中KLF-4 mRNA水平，但对HCT-15细胞中KLF-4表达的影响极小。这些诱导的反应被抑制的共治疗与过氧化物酶体增殖物激活受体γ拮抗剂。这第一次表明，源自大黄酸的PPAR γ激动剂通过受体依赖性途径诱导细胞依赖性小窝蛋白-1和KLF-4表达。
Glycyrrhizin, a pentacyclic triterpene glycoside, is the major phytochemical in licorice. This compound and its hydrolysis product glycyrrhetinic acid have been associated with the multiple therapeutic properties of licorice extracts. We have investigated the effects of 2-cyano substituted analogues of glycyrrhetinic acid on their cytotoxicities and activity as selective peroxisome pro I if erator -activated receptor gamma (PPAR gamma) agonists. Methyl 2-cyano-3,11-dioxo-18 beta-olean-1,12-dien-30-oate (beta-CDODA-Me) and methyl 2-cyano-3,11-dioxo-18 alpha-olean-1,12-dien-30-oate (alpha-CDODA-Me) were more cytotoxic to colon cancer cells than their descyano analogues and introduction of the 2-cyano group into the pentacyclic ring system was necessary for the PPAR gamma agonist activity of alpha-CDODA-Me and beta-CDODA-Me isomers. However, in mammalian two-hybrid assays, both compounds differentially induced interactions of PPAR gamma with coactivators, suggesting that these isomers, which differ only in the stereochemistry at C18 which affects conformation of the E-ring, are selective receptor modulators. This selectivity in colon cancer cells was shown for the induction of two proapoptotic proteins, namely caveolin-1 and the tumor-suppressor gene Kruppel-like factor-4 (KLF-4). beta-CDODA-Me but not alpha-CDODA-Me induced caveolin-1 in SW480 colon cancer cells, whereas caveolin-1 was induced by both compounds in HT-29 and HCT-15 colon cancer cells. The CDODA-Me isomers induced KLF-4 mRNA levels in HT-29 and SW480 cells but had minimal effects on KLF-4 expression in HCT-15 cells. These induced responses were inhibited by cotreatment with a PPAR gamma antagonist. This shows for the first time that PPAR gamma agonists derived from glycyrrhetinic acid induced cell-dependent caveolin-1 and KLF-4 expression through receptor-dependent pathways.