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Research Articles: Therapeutics, Targets, and Development

Inhibition of cell growth and nuclear factor-B activity in pancreatic cancer cell lines by a tylophorine analogue, DCB-3503

¹ Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut; ² National Institute of Cancer Research, National Health Research Institutes, Taipei, Taiwan; and ³ Department of Chemistry, The University of Tennessee, Knoxville, Tennessee

Requests for reprints: Yung-Chi Cheng, Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510. Phone: 203-785-7118; Fax: 203-785-7129. E-mail: yccheng{at}yale.edu

Abstract

A tylophorine analogue, DCB-3503, has been shown to have potent activity against tumor growth in vitro and in vivo, as well as activity in an autoimmune disease model in vivo. This study focuses on investigating the mechanisms responsible for antitumor activity of DCB-3503. The concentrations for inhibiting 50% growth/colony formation ability are 50/162 and 40/149 nmol/L for PANC-1 and HPAC cells, respectively. The growth inhibition effects are associated with DCB-3503-induced reprogramming of tumor cells. DCB-3503 could interfere with cell cycle progression. Several cell cycle regulatory proteins, including cyclin D₁, are down-regulated by DCB-3503. Using several different transcription elements coupled with a reporter gene, it was found that the nuclear factor-B (NF-B) signaling pathway is the most sensitive pathway mediator affected by DCB-3503. The inhibition of NF-B activity is dependent on the down-regulation of nuclear phosphorylated p65, a component of the active form of the NF-B complex. Such a decrease in nuclear phosphorylated p65 can be reversed by a proteosome inhibitor. Furthermore, the activity and protein expression of nuclear IB kinase , which is responsible for p65 phosphorylation, is suppressed and down-regulated in cells treated with DCB-3503. In summary, DCB-3503 could affect cell cycle regulatory proteins and is a potent modulator of NF-B function. It is a potentially useful compound in the management of cancers in which cyclin D1 overexpression and high NF-B activity play a pivotal role. [Mol Cancer Ther 2006;5(10):2484–93]

Grant support: NIH grant R01 CA87863.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Y-C. Cheng is a Fellow of the National Foundation for Cancer Research.

Received 3/17/06; revised 7/25/06; accepted 8/16/06.