Document Detail

TW-37, a small-molecule inhibitor of Bcl-2, inhibits cell growth and induces apoptosis in pancreatic cancer: involvement of Notch-1 signaling pathway.
MedLine Citation:
PMID:  19318573     Owner:  NLM     Status:  MEDLINE    
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.
Zhiwei Wang; Asfar Sohail Azmi; Aamir Ahmad; Sanjeev Banerjee; Shaomeng Wang; Fazlul H Sarkar; Ramzi M Mohammad
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-03-24
Journal Detail:
Title:  Cancer research     Volume:  69     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2009 Apr 
Date Detail:
Created Date:  2009-04-02     Completed Date:  2009-06-02     Revised Date:  2013-12-26    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2757-65     Citation Subset:  IM    
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MeSH Terms
Apoptosis / drug effects
Benzamides / pharmacology*
Cell Growth Processes / drug effects
Cell Line, Tumor
DNA, Complementary / genetics
Down-Regulation / drug effects
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*
Xenograft Model Antitumor Assays
Grant Support
5R01CA101870/CA/NCI NIH HHS; R01 CA101870/CA/NCI NIH HHS; R01 CA109389/CA/NCI NIH HHS; R01CA109389/CA/NCI NIH HHS; U19 CA113317/CA/NCI NIH HHS; U19CA113317/CA/NCI NIH HHS
Reg. No./Substance:
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

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