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一种缬草酯的新型衍生物抑制 PI3K/AKT 通路，并在人胰腺癌细胞中引起 Noxa 依赖性细胞凋亡。

A novel derivative of valepotriate inhibits the PI3K/AKT pathway and causes Noxa-dependent apoptosis in human pancreatic cancer cells.

机构信息

Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People's Hospital, Zhejiang Chinese Medical University, Hangzhou, 310006, China.

Translational Medicine Research Center, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.

出版信息

Acta Pharmacol Sin. 2020 Jun;41(6):835-842. doi: 10.1038/s41401-019-0354-1. Epub 2020 Feb 11.

DOI:10.1038/s41401-019-0354-1
PMID:32047260
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7470838/
Abstract

Natural compound valepotriate exhibits inhibitory activity against a number of cancers, but the effect of valepotriate against pancreatic cancer is unclear, and the structure-activity relationship of valepotriate has not been characterized. In this study, we performed a structure-based similarity search and found 16 hit compounds. Among the 16 hits, (1S,6S,7R)-6-(acetyloxy)-1-[(3-methylbutanoyl)oxy]-4a,5,6,7a-tetrahydro-1H-spiro[cyclopenta[c]pyran-7,2'-oxiran]-4-ylmethyl 3-methylbutanoate (denoted as Amcp) exhibited superior anticancer activity against human pancreatic cancer BxPC-3 and SW1990 cells. The anti-proliferation activity of Amcp was validated in human pancreatic cancer BxPC-3 and SW1990 cells in vitro. Amcp more effectively induced apoptosis in BxPC-3 and SW1990 cells than gemcitabine. At a concentration of 15 μM, Amcp significantly suppressed the PI3K/AKT pathway and disrupted the mitochondrial membrane equilibrium through modulation of Noxa and Mcl-1 balance in both cell lines. Meanwhile, knockdown of Noxa substantially attenuated Amcp-induced reduction of cell viability and anti-apoptotic protein Mcl-1 level in BxPC-3 cells. In addition, Amcp showed synergistic anticancer effects when combined with gemcitabine in BxPC-3 cells. To conclude, this work not only suggests that Amcp possesses a dual-inhibitory activity towards PI3K/AKT pathway and Mcl-1, but also enlightens further development of bioactive valepotriate derivatives.

摘要

天然化合物缬草酯对多种癌症具有抑制活性，但缬草酯对胰腺癌的作用尚不清楚，其构效关系也尚未确定。在本研究中，我们进行了基于结构的相似性搜索，找到了 16 个命中化合物。在这 16 个命中化合物中，（1S，6S，7R）-6-（乙酰氧基）-1-[(3-甲基丁酰基）氧基]-4a，5，6，7a-四氢-1H-螺[环戊烷[c]吡喃-7,2'-环氧]-4-基甲基 3-甲基丁酸盐（表示为 Amcp）对人胰腺癌细胞 BxPC-3 和 SW1990 表现出优异的抗癌活性。Amcp 在体外对人胰腺癌细胞 BxPC-3 和 SW1990 的抗增殖活性进行了验证。与吉西他滨相比，Amcp 更有效地诱导 BxPC-3 和 SW1990 细胞凋亡。在 15μM 浓度下，Amcp 显著抑制了 PI3K/AKT 通路，并通过调节 Noxa 和 Mcl-1 在两种细胞系中的平衡破坏了线粒体膜平衡。同时，在 BxPC-3 细胞中敲低 Noxa 可显著减弱 Amcp 诱导的细胞活力降低和抗凋亡蛋白 Mcl-1 水平降低。此外，Amcp 与吉西他滨联合使用在 BxPC-3 细胞中表现出协同的抗癌作用。总之，这项工作不仅表明 Amcp 对 PI3K/AKT 通路和 Mcl-1 具有双重抑制活性，而且为进一步开发缬草酯生物活性衍生物提供了启示。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/005f/7656574/b539852764e0/41401_2019_354_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/005f/7656574/05ea60a695e4/41401_2019_354_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/005f/7656574/c0fa33fb61a0/41401_2019_354_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/005f/7656574/b539852764e0/41401_2019_354_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/005f/7656574/05ea60a695e4/41401_2019_354_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/005f/7656574/c0fa33fb61a0/41401_2019_354_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/005f/7656574/b539852764e0/41401_2019_354_Fig4_HTML.jpg

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