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Division of Cellular and Molecular Pathogenesis, Department of Pathology, Medical College of Virginia Campus of Virginia Commonwealth University, Richmond, Virginia 23298-0297

² To whom requests for reprints should be addressed, at Department of Pathology, Medical College of Virginia Campus, Virginia Commonwealth, University, P. O. Box 980297, Richmond, VA 23298-0297. Phone: (804) 828-9549; Fax: (804) 828-9749; E-mail: asirica{at}hsc.vcu.edu

Emodin, a tyrosine kinase inhibitor, effectively blocked tyrosine phosphorylation of p185^neu overexpressed in cultured rat C611B cholangiocarcinoma (ChC) cells and in neu-transformed WB-F344 rat-liver epithelial stem-like cells (WBneu cells). Celecoxib, a cyclooxygenase-2 inhibitor, markedly decreased prostaglandin (PG) levels overproduced by these respective neoplastically transformed liver cell types but was without effect in inhibiting PG production by untransformed WB-F344 cells that do not express detectable cyclooxygenase-2 protein. Notably, in combination, emodin (30 µM) and celecoxib (35 µM) acted synergistically to significantly suppress anchorage-dependent and -independent growth of C611B ChC cells and of WBneu cells over treatments with either agent alone. This prominent suppression of cell growth correlated with significant increases in the activation of caspases-9 and -3 and induction of apoptosis in the combination-treated cells, which was associated with an enhanced suppression of Akt activation. Here it is important to note that the concentration of celecoxib needed to suppress growth and induce apoptosis in the C611B and WBneu cells was markedly higher than that needed to effectively inhibit PG production by these malignant cell types. Thus, our data indicate that celecoxib is acting independently of its ability to inhibit cyclooxygenase-2 activity in suppressing growth of C611B and WBneu cells in vitro. Furthermore, our findings strongly suggest that increased inhibition of the antiapoptotic kinase Akt activation produced by the emodin/celecoxib combination treatment plays a key role in the mechanism by which this drug combination acts to enhance cell growth suppression and apoptosis in cultured C611B ChC cells and WBneu cells.

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