Cardenolides as Inhibitors of Hypoxia-Inducible Factor-1 Transcriptional Activity

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• 英文论文题名：Cardenolides as Inhibitors of Hypoxia-Inducible Factor-1 Transcriptional Activity
• 论文作者：Li-Ping Bai ; Supawadee Parhira ; Ming Chen ; Guo-Yuan Zhu ; Zhi-Hong Jiang
• 英文论文作者：Li-Ping Bai ; Supawadee Parhira ; Ming Chen ; Guo-Yuan Zhu ; Zhi-Hong Jiang ; State Key Laboratory of Quality Research in Chinese Medicine ; Macau University of Science and Technology
• 年：2016
• 作者机构：State Key Laboratory of Quality Research in Chinese Medicine,Macau University of Science and Technology;
• 英文论文关键词：Cardenolide ; Calotropis gigantea ; HIF-1 ; inhibitor ; anti-cancer activity
• 会议召开时间：2016-07-01
• 会议录名称：中国化学会第30届学术年会摘要集-第二十八分会：化学生物学
• 语种：英文
• 分类号：R96
• 学会代码：ZGHY
• 会议名称：中国化学会第30届学术年会-第二十八分会 ; 化学生物学
• 会议地点：中国辽宁大连
• 主办单位：中国化学会
• 学会名称：中国化学会
• 页数：1
• 文件大小：133k
• 原文格式：D
• 会议级别：全国

摘要

Hypoxia of solid tumors originates from the aberrant cell proliferation from an imbalance between oxygen supply and consumption.Hypoxia-inducible factor 1(HIF-1)is a principal transcription factor by which tumor cells adapt to the low oxygen microenvironment,and has been considered as a potential target for the development of anticancer agents~1.Our previous study has reported the potent inhibitory effects of a pair of cardenolide epimers,uscharin and 2'-epi-uscharin~2,on HIF-1 transcriptional activity.As a continuous research,18 known cardenolides(Fig.1)were isolated and identified from the medicinal plant Calotropis gigantea(Asclepiadaceae)~3.All of these18 cardenolides were evaluated for inhibitory effect on HIF-1 transcriptional activity by using a T47D cell-based co-transfected firefly and Renilla luciferase reporter assay~2.Digoxin,a well-known HIF-1 inhibitor was used as a positive control.As a result,seven cardenolides exhibited stronger HIF-1 inhibitory activities than that of digoxin with IC_(50)values in nanomolar potency(28.6-64.8 nM).An analysis of structure-activity relationship of cardenolides and their HIF-1 inhibitory activities revealed the great contribution of a β-configuration of the substituents at positions C-2' and C-3',an aldehydic moiety on C-19,and the dioxane moiety between the aglycone and sugar part of cardenolides.In contrast,the presence of a hydroxyl group at positions C-15,C-16 and C-4,in the chemical structures of cardenolides appeared to reduce such activity.Further cytotoxic bioassay confirmed that all the above seven cardenolides showed more potent cytotoxic effects on breast cancer cell MCF-7 with IC_(50)values of 30-68.8 nM than that of digoxin(IC_(50)of 124.5 nM).In addition,all these seven cardenolides exhibited much stronger cytotoxic effects on MCF-7 cell than taxol.This study demonstrated the promising potential of cardenolides from Calotropis gigantea as inhibitors of HIF-1 transcriptional activity.
Hypoxia of solid tumors originates from the aberrant cell proliferation from an imbalance between oxygen supply and consumption.Hypoxia-inducible factor 1(HIF-1)is a principal transcription factor by which tumor cells adapt to the low oxygen microenvironment,and has been considered as a potential target for the development of anticancer agents~1.Our previous study has reported the potent inhibitory effects of a pair of cardenolide epimers,uscharin and 2'-epi-uscharin~2,on HIF-1 transcriptional activity.As a continuous research,18 known cardenolides(Fig.1)were isolated and identified from the medicinal plant Calotropis gigantea(Asclepiadaceae)~3.All of these18 cardenolides were evaluated for inhibitory effect on HIF-1 transcriptional activity by using a T47D cell-based co-transfected firefly and Renilla luciferase reporter assay~2.Digoxin,a well-known HIF-1 inhibitor was used as a positive control.As a result,seven cardenolides exhibited stronger HIF-1 inhibitory activities than that of digoxin with IC_(50)values in nanomolar potency(28.6-64.8 nM).An analysis of structure-activity relationship of cardenolides and their HIF-1 inhibitory activities revealed the great contribution of a β-configuration of the substituents at positions C-2' and C-3',an aldehydic moiety on C-19,and the dioxane moiety between the aglycone and sugar part of cardenolides.In contrast,the presence of a hydroxyl group at positions C-15,C-16 and C-4,in the chemical structures of cardenolides appeared to reduce such activity.Further cytotoxic bioassay confirmed that all the above seven cardenolides showed more potent cytotoxic effects on breast cancer cell MCF-7 with IC_(50)values of 30-68.8 nM than that of digoxin(IC_(50)of 124.5 nM).In addition,all these seven cardenolides exhibited much stronger cytotoxic effects on MCF-7 cell than taxol.This study demonstrated the promising potential of cardenolides from Calotropis gigantea as inhibitors of HIF-1 transcriptional activity.

引文

1.Harris,A.L.Nature Review Cancer 2002,2(1):38
    2.Parhira,S.;Zhu,G.-Y.;Jiang,R.-W.;Liu,L.;Bai,L.-P.;Jiang,Z.-H.Scientific Reports 2014,4:4748
    3.Parhira,S.;Zhu,G.-Y.;Li,T;Liu,L.;Bai,L.-P.;Jiang,Z.-H.Chinese Medicine 2016,11:9