A novel synthetic oleanolic acid derivative with amino acid conjugate suppresses tumour growth by inducing cell cycle arrest
A novel synthetic oleanolic acid derivative with amino acid conjugate suppresses tumour growth by inducing cell cycle arrest
复制标题
一种具有氨基酸缀合物的新型合成齐墩果酸衍生物通过诱导细胞周期停滞来抑制肿瘤生长
DOI：
10.1211/jpp.59.8.0005
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发表时间：
2007-08-01
影响因子：
3.3
通讯作者：
Xu, Qiang
中科院分区：
文献类型：
--
作者：
Lu, Xiao-Min;Yi, Hong-Wei;Xu, Qiang
油酸（3 β-羟基-齐墩果-12-烯-28-酸; OA）具有多种生物活性，在许多亚洲国家用于药用目的。已经合成了OA的各种衍生物以试图提高效力。在这里，我们描述了一种新的OA衍生物，N-[（3 β）-3-（乙酰氧基）-28-氧代-12-烯-28-基]-甘氨酸甲酯（AOA-GMe）的抗肿瘤活性。无论是在体外还是在体内，AOA-GMe都是比其母体化合物OA更有效的B16黑色素瘤细胞生长抑制剂。AOA-GMe对人K562白血病细胞也表现出剂量依赖性抑制，但对正常人外周血单核细胞几乎没有毒性。AOA-GMe诱导细胞周期停滞在G 0/G1期，并阻断G1-S转换，这与细胞周期蛋白D、细胞周期蛋白依赖性激酶CDK 4和磷酸化视网膜母细胞瘤蛋白水平的显著降低以及细胞周期蛋白依赖性激酶抑制剂p15水平的增加密切相关。OA未显示此类活动。这些结果表明，AOA-GMe可以通过调节参与细胞周期的蛋白质来诱导肿瘤细胞的生长停滞。
Oleanolic acid (3 beta-hydroxy-olean-12-en-28-oic acid; OA) has a wide variety of bioactivities and is used for medicinal purposes in many Asian countries. Various derivatives of OA have been synthesized in attempts to improve the potency. Here we describe the anti-tumour activity of a novel OA derivative, N-[(3 beta)-3-(acetyloxy)-28-oxoolean-12-en-28-yl]-glycine methyl ester (AOA-GMe). AOA-GMe was a more potent inhibitor of the growth of B16 melanoma cells than its parent compound OA, both in-vitro and in-vivo. AOA-GMe also exhibited dose-dependent inhibition of human K562 leukaemia cells, but had almost no toxicity in normal human peripheral blood mononuclear cells. AOA-GMe induced cell cycle arrest in G0/G1 and blocked G1-S transition, which correlated well with marked decreases in levels of cyclin D, cyclin-dependent kinase CDK4 and phosphorylated retinoblastoma protein, and increases in the cyclin-dependent kinase inhibitor p15. OA did not show such activities. These results suggest that AOA-GMe may induce growth arrest in tumour cells through regulation of proteins involved in the cell cycle.