Characterization of a novel curcumin analog P1 as potent inhibitor of the NF-kappa B signaling pathway with distinct mechanisms

doi:10.1038/aps.2013.2

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	Characterization of a novel curcumin analog P1 as potent inhibitor of the NF-kappa B signaling pathway with distinct mechanisms
	Peng, Yan-min 1; Zheng, Jian-bin 2; Zhou, Yu-bo1 ; Li, Jia1
刊名	ACTA PHARMACOLOGICA SINICA
	2013-07
卷号	34 期号:7 页码:939-950
关键词	curcumin P1 anticancer agent high-throughput screen NF-kappa B HeLa cell mitochondria ROS
ISSN号	1671-4083
DOI	10.1038/aps.2013.2
文献子类	Article
英文摘要	Aim: Curcumin has shown promising anticancer activity, which relies on its inhibition on NF-kappa B pathway. In this study, we characterized the pharmacological profile of a novel curcumin analog P1 and elucidate the related mechanisms. Methods: HEK293/NF-kappa B cells, stably transfected with an NF-kappa B-responsive luciferase reporter plasmid, were generated for high-throughput screen (HTS). Eight cancer cell lines, including PC3, COLO 205, HeLa cells etc. were tested. Cell viability was assessed using the sulforhodamine B (SRB) assays. Cell apoptosis was evaluated using FACS, immunocytochemistry, and Western blotting. H-2-DCFDA and MitoSOX Red were used to detect cellular and mitochondrial reactive oxygen species (ROS). The mitochondrial function was evaluated using mitochondrial oxygen consumption assay. Results: P1, a tropinone curcumin, was found in HTS targeting the NF-kappa B pathway. Its IC50 value in inhibition of TNF-alpha-induced NF-kappa B activation was 0.8 mu mol/L, whereas its IC50 values in inhibiting the growth of A549 and HeLa cells were 1.24 and 0.69 mu mol/L, respectively, which was 20- to 30-fold more potent than curcumin. The inhibition of P1 on the NF-kappa B pathway was further addressed in HeLa cells. The compound up to 10 mu mol/L did not affect the binding of NF-kappa B to DNA, but markedly inhibited NF-kappa B nuclear translocation, I kappa B degradation and I kappa B kinase phosphorylation. The compound (1 and 3 mu mol/L) concentration-dependently induced ROS generation, whereas curcumin up to 20 mu mol/L had no effect. P1-induced ROS generation was mainly localized in mitochondria, and reversed by NAC. Moreover, the compound significantly enhanced TNF-alpha-induced apoptosis. Conclusion: P1 is a novel curcumin analog with potent anticancer activities, which exerts a distinct inhibition on the NF-kappa B pathway.
资助项目	National Natural Science Foundation of China[91029716] ; National Natural Science Foundation of China[81021062] ; National Natural Science Foundation of China[81072667]
WOS关键词	ACTIVATED PROTEIN-KINASE ; REGULATED GENE-PRODUCTS ; PANCREATIC-CANCER ; TNF-ALPHA ; OXIDATIVE STRESS ; TUMOR-CELLS ; APOPTOSIS ; PROLIFERATION ; SUPPRESSION ; EXPRESSION
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:4874888
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000321332700010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277556]
专题	国家新药筛选中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Zhou, Yu-bo
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China; 2.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China
推荐引用方式 GB/T 7714	Peng, Yan-min,Zheng, Jian-bin,Zhou, Yu-bo,et al. Characterization of a novel curcumin analog P1 as potent inhibitor of the NF-kappa B signaling pathway with distinct mechanisms[J]. ACTA PHARMACOLOGICA SINICA,2013,34(7):939-950.
APA	Peng, Yan-min,Zheng, Jian-bin,Zhou, Yu-bo,&Li, Jia.(2013).Characterization of a novel curcumin analog P1 as potent inhibitor of the NF-kappa B signaling pathway with distinct mechanisms.ACTA PHARMACOLOGICA SINICA,34(7),939-950.
MLA	Peng, Yan-min,et al."Characterization of a novel curcumin analog P1 as potent inhibitor of the NF-kappa B signaling pathway with distinct mechanisms".ACTA PHARMACOLOGICA SINICA 34.7(2013):939-950.