Document Detail


Anti-cancer effects of JKA97 are associated with its induction of cell apoptosis via a Bax-dependent and p53-independent pathway.
MedLine Citation:
PMID:  18218619     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
p53, one of the most commonly mutated genes in human cancers, is thought to be associated with cancer development. Hence, screening and identifying natural or synthetic compounds with anti-cancer activity via p53-independent pathway is one of the most challenging tasks for scientists in this field. Compound JKA97 (methoxy-1-styryl-9H-pyrid-[3,4-b]-indole) is a small molecule synthetic anti-cancer agent, with unknown mechanism(s). In this study we have demonstrated that the anti-cancer activity of JKA97 is associated with apoptotic induction via p53-independent mechanisms. We found that co-incubation of human colon cancer HCT116 cells with JKA97 inhibited HCT116 cell anchorage-independent growth in vitro and tumorigenicity in nude mice and also induced a cell apoptotic response, both in the cell culture model and in a tumorigenesis nude mouse model. Further studies showed that JKA97-induced apoptosis was dramatically impaired in Bax knock-out (Bax(-/-)) HCT116 cells, whereas the knock-out of p53 or PUMA did not show any inhibitory effects. The p53-independent apoptotic induction by JKA97 was confirmed in other colon cancer and hepatocarcinoma cell lines. In addition, our results showed an induction of Bax translocation and cytochrome c release from the mitochondria to the cytosol in HCT116 cells, demonstrating that the compound induces apoptosis through a Bax-initiated mitochondria-dependent pathway. These studies provide a molecular basis for the therapeutic application of JKA97 against human cancers with p53 mutations.
Authors:
Wenjing Luo; Jinyi Liu; Jingxia Li; Dongyun Zhang; Mingchao Liu; James K Addo; Shivaputra Patil; Lin Zhang; Jian Yu; John K Buolamwini; Jingyuan Chen; Chuanshu Huang
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-01-23
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  283     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-24     Completed Date:  2008-05-20     Revised Date:  2013-06-06    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8624-33     Citation Subset:  IM    
Affiliation:
Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects*
Apoptosis Regulatory Proteins / genetics,  metabolism
Body Weight / drug effects
Carbolines / chemistry,  pharmacology*
Cell Line, Tumor
Female
Humans
Mice
Mice, Nude
Molecular Structure
Neoplasms / genetics,  metabolism*,  pathology*
Protein Transport
Proto-Oncogene Proteins / genetics,  metabolism
Styrenes / chemistry,  pharmacology*
Tumor Suppressor Protein p53 / genetics,  metabolism
Xenograft Model Antitumor Assays
bcl-2-Associated X Protein / genetics,  metabolism*
Grant Support
ID/Acronym/Agency:
CA 094964/CA/NCI NIH HHS; CA 1002102/CA/NCI NIH HHS; CA 103180/CA/NCI NIH HHS; CA 112557/CA/NCI NIH HHS; ES 000260/ES/NIEHS NIH HHS; ES 012451/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/1-styryl-9H-pyrido(3,4-b)indole; 0/Apoptosis Regulatory Proteins; 0/BBC3 protein, human; 0/Carbolines; 0/Proto-Oncogene Proteins; 0/Styrenes; 0/Tumor Suppressor Protein p53; 0/bcl-2-Associated X Protein
Comments/Corrections
Erratum In:
J Biol Chem. 2012 Jul 6;287(28):23850

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