Antiproliferative and Apoptotic Activities of Triterpenoid Saponins from the Roots of Platycodon grandiflorum and Their Structure-Activity Relationships
Antiproliferative and Apoptotic Activities of Triterpenoid Saponins from the Roots of Platycodon grandiflorum and Their Structure-Activity Relationships
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DOI：
10.1055/s-0032-1328401
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发表时间：
2013-05-01
期刊：
影响因子：
2.7
通讯作者：
Kim, Yeong Shik
中科院分区：
文献类型：
--
作者：
Chun, Jaemoo;Ha, In Jin;Kim, Yeong Shik
本研究旨在研究桔梗皂苷（包括桔梗皂苷D、2“-O-乙酰基桔梗皂苷D、3”-O-乙酰基桔梗皂苷D、远志皂苷D、2“-O-乙酰基远志皂苷D和3”-O-乙酰基远志皂苷D）和缺失C-3或C-28糖残基的原皂苷配基的抗增殖和凋亡活性，从桔梗皂苷D的水解得到。我们还阐明了这些分子的结构-活性关系，以定义对桔梗皂苷和原皂苷元的生物活性至关重要的结构特征。结果表明，所有桔梗皂苷对所测试的七种类型的癌细胞系具有抗增殖作用。特别地，在鼠李糖的C-2或C-3位置处的0-乙酰化和在C-24处的脱羟基化增加了化合物的细胞毒性，而与C-3或C-28连接的糖残基的损失显著降低了细胞毒性。这种细胞毒性与细胞凋亡有关，这是由DNA片段化，磷脂酰丝氨酸外化，以及AGS细胞中半胱天冬酶的激活所指示的。此外，桔梗皂苷还能抑制Akt的磷酸化，从而抑制mTOR和NF-κ B信号通路，进而抑制其下游蛋白的表达。总之，六种桔梗皂苷具有抗增殖活性，并且糖残基、鼠李糖上的O-乙酰基和C-4处的甲基的存在有助于它们的细胞毒性和凋亡活性。这些发现可能有助于评价桔梗皂苷的构效关系，并将其作为一种有效的诱导凋亡剂进行修饰。
The present study was undertaken to investigate the antiproliferative and apoptotic activities of Platycodon saponins, including platycodin D, 2 ''-O-acetylplatycodin D, 3 ''-O-acetylplatycodin D, polygalacin D, 2 ''-O-acetylpolygalacin D, and 3 ''-O-acetylpolygalacin D, isolated from Platycodon grandiflorum, and prosapogenins which lack the C-3 or C-28 sugar residues, obtained from hydrolysis of platycodin D. We also clarified the structure-activity relationships of these molecules to define structural features that are crucial for the biological activity of Platycodon saponins and prosapogenins. The results showed that all Platycodon saponins had antiproliferative effects on the seven types of cancer cell lines tested. In particular, O-acetylation at the C-2 or C-3 position of rhamnose and dehydroxylation at C-24 increase the compound's cytotoxicity, while the loss of sugar residues linked to C-3 or C-28 dramatically reduced cytotoxicity. This cytotoxicity was associated with apoptosis, which was indicated by DNA fragmentation, phosphatidylserine externalization, and the activation of caspases in AGS cells. Furthermore, Platycodon saponins suppressed the phosphorylation of Akt, which resulted in the inhibition of mTOR and NF-kappa B signaling following the inhibition of their downstream proteins. In conclusion, six Platycodon saponins have antiproliferative activity, and the presence of sugar residues, an O-acetyl group on the rhamnose, and a methyl group at C-4 contributes to their cytotoxicity and apoptotic activity. These findings may be useful in evaluating the structure-activity relationships of Platycodon saponins and modifying them as a potent apoptosis-inducing agent.