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TW-37, a Small-Molecule Inhibitor of Bcl-2, Inhibits Cell Growth and Induces Apoptosis in Pancreatic Cancer: Involvement of Notch-1 Signaling Pathway

¹ Department of Pathology and ² Division of Hematology and Oncology, Department of Internal Medicine, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan; and ³ Departments of Internal Medicine, Pharmacology and Medicinal Chemistry, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan

Requests for reprints: Ramzi M. Mohammad, Division of Hematology and Oncology, Department of Internal Medicine, Karmanos Cancer Institute, Wayne State University School of Medicine, 732 HWCRC, 4100 John R. Street, Detroit, MI 48201. Phone: 313-576-8329; Fax: 313-576-8389; E-mail: Mohammar{at}karmanos.org.

Key Words: Bcl-2 • Notch-1 • pancreatic cancer

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 -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. [Cancer Res 2009;69(7):2757–65]

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