title: TW-37, a small-molecule inhibitor of Bcl-2, inhibits cell growth and induces apoptosis in pancreatic cancer: involvement of Notch-1 signaling pathway.
abstract: 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.
authors.affiliation: Department of Pathology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Wang
authors.forename: Asfar Sohail
authors.initials: AS
authors.lastname: Azmi
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmad
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Banerjee
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
authors.forename: Ramzi M
authors.initials: RM
authors.lastname: Mohammad