Daphnane Diterpenoids from Daphne genkwa Inhibit PI3K/Akt/mTOR Signaling and Induce Cell Cycle Arrest and Apoptosis in Human Colon Cancer Cells.,Journal of Natural Products

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Daphnane Diterpenoids from Daphne genkwa Inhibit PI3K/Akt/mTOR Signaling and Induce Cell Cycle Arrest and Apoptosis in Human Colon Cancer Cells.
Journal of Natural Products ( IF 3.3 ) Pub Date : 2020-03-30 , DOI: 10.1021/acs.jnatprod.0c00003
Rong-Rong Pan ₁ , Chun-Yan Zhang ₁ , Yuan Li ₁ , Bing-Bing Zhang ₁ , Liang Zhao ₁ , Ying Ye ₁ , Ya-Nan Song ₁ , Miao Zhang ₁ , Hong-Yun Tie ₁ , Hong Zhang _{1,

2} , Jian-Yong Zhu ₁

Affiliation

Seven new daphnane-type diterpenoids, daphgenkins A-G (1-7), and 15 known analogues (8-22) were isolated from the flower buds of Daphne genkwa. Their structures and absolute configurations were elucidated by spectroscopic data and calculated ECD analyses. The cytotoxicities of all daphnane-type diterpenoids (1-22) obtained were evaluated against three human colon cancer cell lines (SW620, RKO, and LoVo). Compounds 1, 12, and 13 exhibited cytotoxic effects against the SW620 and RKO cell lines, with IC50 values in the range of 3.0-9.7 μM. The most active new compound, 1, with an IC50 value of 3.0 μM against SW620 cells, was evaluated further for its underlying molecular mechanism. Compound 1 induced G0/G1 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 1 significantly inhibited PI3K/Akt/mTOR signaling in SW620 cells. Together, the results suggest that compound 1 may be a suitable lead compound for further biological evaluation.

中文翻译：

达芙妮根中的达芙烷双萜类化合物抑制PI3K / Akt / mTOR信号传导并诱导人结肠癌细胞的细胞周期阻滞和凋亡。

从达芙妮根花的花蕾中分离出了七个新的达芙烷型二萜类化合物，达芙庚金素AG（1-7）和15个已知类似物（8-22）。通过光谱数据和计算的ECD分析阐明了它们的结构和绝对构型。评价了获得的所有达芬烷型二萜类化合物（1-22）对三种人类结肠癌细胞系（SW620，RKO和LoVo）的细胞毒性。化合物1、12和13对SW620和RKO细胞系表现出细胞毒性作用，IC50值在3.0-9.7μM的范围内。对SW620细胞的IC50值为3.0μM的最具活性的新化合物1，对其潜在的分子机理作了进一步评估。化合物1诱导G0 / G1细胞周期停滞，导致SW620细胞凋亡的诱导。而且，它通过增加Bax / Bcl-2的比例来诱导癌细胞凋亡，激活裂解的caspase-3和caspase-9，并上调PARP。最后，化合物1显着抑制SW620细胞中的PI3K / Akt / mTOR信号传导。总之，结果表明化合物1可能是用于进一步生物学评估的合适的先导化合物。

更新日期：2020-03-30

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