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

查看全文 作　　者：You-you [1,2]Yan;Ke-yu [1,2,3]Shi;Fei [1,2,3]Teng;Jing [3]Chen;Jin-xin [4]Che;Xiao-wu [4]Dong;Neng-ming [1,2,3]Lin;Bo [1,2]Zhang

机构地区：[1]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;[2]Translational Medicine Research Center,Affiliated Hangzhou First People's Hospital,Zhejiang University School of Medicine,Hangzhou 310006,China;[3]College of Pharmaceutical Sciences,Zhejiang Chinese Medical University,Hangzhou 311402,China;[4]U-ENS Joint Laboratory of Medicinal Chemistry,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,China

出　　处：《Acta Pharmacologica Sinica》索引2020年第41卷第6期,共8页

基　　金：This study was supported by Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province,the Hangzhou Major Science and Technology Project(20172016A01);the Clinical Pharmacy of Zhejiang Key Medical Disciplines(2018-2-3);the Clinical Pharmacy of Hangzhou Key Medical Disciplines(2017-68-7);the Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talent(2010-190-4,NL);and the Natural Science Foundation of Zhejiang Province(LY20H310005,LY19H310004,and LY19H300001). 摘　　要：Natural compound valepotriate exhibits inhibitory activity against a number of cancers,but the effect of valepotdriate 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 15μM,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. 关键词：valepotriate human pancreatic cancer PI3K/AKT NOXA MCL-1

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

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