| Anti-cancer effects of JKA97 are associated with its induction of cell apoptosis via a Bax-dependent and p53-independent pathway. | |
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MedLine Citation:
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PMID: 18218619 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2008-01-23 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 283 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2008 Mar |
Date Detail:
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Created Date: 2008-03-24 Completed Date: 2008-05-20 Revised Date: 2012-09-10 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 8624-33 Citation Subset: IM |
Affiliation:
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Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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:
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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:
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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:
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J Biol Chem. 2012 Jul 6;287(28):23850 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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