| TW-37, a small-molecule inhibitor of Bcl-2, inhibits cell growth and induces apoptosis in pancreatic cancer: involvement of Notch-1 signaling pathway. | |
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MedLine Citation:
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PMID: 19318573 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Overexpression of Bcl-2 family proteins has been found in a variety of aggressive human carcinomas, including pancreatic cancer, suggesting that specific agents targeting Bcl-2 family proteins would be valuable for pancreatic cancer therapy. We have previously reported that TW-37, a small-molecule inhibitor of Bcl-2 family proteins, inhibited cell growth and induced apoptosis in pancreatic cancer. However, the precise role and the molecular mechanism of action of TW-37 have not been fully elucidated. In our current study, we found that TW-37 induces cell growth inhibition and S-phase cell cycle arrest, with regulation of several important cell cycle-related genes like p27, p57, E2F-1, cdc25A, CDK4, cyclin A, cyclin D1, and cyclin E. The cell growth inhibition was accompanied by increased apoptosis with concomitant attenuation of Notch-1, Jagged-1, and its downstream genes such as Hes-1 in vitro and in vivo. We also found that down-regulation of Notch-1 by small interfering RNA or gamma-secretase inhibitors before TW-37 treatment resulted in enhanced cell growth inhibition and apoptosis. Our data suggest that the observed antitumor activity of TW-37 is mediated through a novel pathway involving inactivation of Notch-1 and Jagged-1. |
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Authors:
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Zhiwei Wang; Asfar Sohail Azmi; Aamir Ahmad; Sanjeev Banerjee; Shaomeng Wang; Fazlul H Sarkar; Ramzi M Mohammad |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2009-03-24 |
Journal Detail:
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Title: Cancer research Volume: 69 ISSN: 1538-7445 ISO Abbreviation: Cancer Res. Publication Date: 2009 Apr |
Date Detail:
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Created Date: 2009-04-02 Completed Date: 2009-06-02 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 2757-65 Citation Subset: IM |
Affiliation:
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Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, 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 Benzamides / pharmacology* Cell Growth Processes / drug effects Cell Line, Tumor DNA, Complementary / genetics Down-Regulation / drug effects Female Humans Mice Mice, SCID Pancreatic Neoplasms / drug therapy*, genetics, metabolism, pathology Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*, genetics RNA, Messenger / biosynthesis, genetics RNA, Small Interfering / genetics Receptor, Notch1 / biosynthesis, genetics, metabolism* S Phase / drug effects Signal Transduction / drug effects Sulfones / pharmacology* Transfection Xenograft Model Antitumor Assays |
| Grant Support | |
ID/Acronym/Agency:
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5R01CA101870/CA/NCI NIH HHS; R01CA109389/CA/NCI NIH HHS; U19CA113317/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Benzamides; 0/DNA, Complementary; 0/NOTCH1 protein, human; 0/Proto-Oncogene Proteins c-bcl-2; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/Receptor, Notch1; 0/Sulfones; 0/TW-37 compound |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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