瑞香烷二萜类化合物通过抑制 PI3K/Akt/mTOR 信号通路诱导人结肠癌细胞周期阻滞和凋亡
Daphnane Diterpenoids from Inhibit PI3K/Akt/mTOR Signaling and Induce Cell Cycle Arrest and Apoptosis in Human Colon Cancer Cells.
机构信息
Central Laboratory, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200137, People's Republic of China.
Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People's Republic of China.
出版信息
J Nat Prod. 2020 Apr 24;83(4):1238-1248. doi: 10.1021/acs.jnatprod.0c00003. Epub 2020 Mar 30.
Seven new daphnane-type diterpenoids, daphgenkins A-G (-), and 15 known analogues (-) were isolated from the flower buds of . Their structures and absolute configurations were elucidated by spectroscopic data and calculated ECD analyses. The cytotoxicities of all daphnane-type diterpenoids (-) obtained were evaluated against three human colon cancer cell lines (SW620, RKO, and LoVo). Compounds , , and exhibited cytotoxic effects against the SW620 and RKO cell lines, with IC values in the range of 3.0-9.7 μM. The most active new compound, , with an IC value of 3.0 μM against SW620 cells, was evaluated further for its underlying molecular mechanism. Compound induced G/G cell cycle arrest, leading to the induction of apoptosis in SW620 cells. Also, it induced cancer cell apoptosis by an increased ratio of Bax/Bcl-2, activated cleaved caspase-3 and caspase-9, and upregulated PARP. Finally, compound significantly inhibited PI3K/Akt/mTOR signaling in SW620 cells. Together, the results suggest that compound may be a suitable lead compound for further biological evaluation.
从 花蕾中分离得到了 7 个新的瑞香烷型二萜类化合物(daphgenkins A-G,-)和 15 个已知类似物(-)。通过光谱数据分析和计算ECD 分析确定了它们的结构和绝对构型。对所有分离得到的瑞香烷型二萜类化合物(-)进行了人结肠癌细胞系(SW620、RKO 和 LoVo)的细胞毒性评价。化合物 、 、 对 SW620 和 RKO 细胞系具有细胞毒性作用,IC 值范围为 3.0-9.7 μM。最具活性的新化合物 ,对 SW620 细胞的 IC 值为 3.0 μM,进一步评估了其潜在的分子机制。化合物 诱导 G/G 细胞周期停滞,导致 SW620 细胞凋亡。此外,它通过增加 Bax/Bcl-2 的比值、激活 cleaved caspase-3 和 caspase-9 以及上调 PARP 诱导癌细胞凋亡。最后,化合物 显著抑制了 SW620 细胞中的 PI3K/Akt/mTOR 信号通路。综上所述,结果表明化合物 可能是进一步进行生物学评价的合适先导化合物。