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The New Sulindac Derivative IND 12 Reverses Ras-induced Cell Transformation¹

Max-Planck-Institut für molekulare Physiologie, 44227 Dortmund, Germany [I-M. K., P. H., S. C., A. K., U. H., M-R. A., O. M.]; Laboratory of Experimental Cancerology, Ghent University Hospital, B-9000 Ghent, Belgium [P. D., M. M.]; Squarix GmbH, 45768 Marl, Germany [K-H. G.]; Klinikum Kreis Herford, Herford, 32045 Germany [G. W.]; and Institut für Zellbiologie (Tumorforschung), Universitätsklinikum Essen, 45122 Essen, Germany [T. M.]

The nonsteroidal anti-inflammatory drug Sulindac has chemopreventiveand antitumorigenic properties. Its metabolites induce apoptosis and inhibit signaling pathways critical for malignant transformation, including the Ras pathway. Here we show that the new Sulindac derivative IND 12 reverses the phenotype of Ras-transformed MDCK-f3 cells and restores an untransformed epithelioid morphology characterized by growth in monolayers with regular cell-cell adhesions. Moreover, IND 12 treatment induces the expression at membranes of the cell adhesion protein E-cadherin and increases the level of the E-cadherin-bound ß-catenin. As a consequence, IND 12-treated MDCK-f3 cells lose their invasion capacity and regain the ability to aggregate. In the presence of IND 12, MDCK-f3 cells show regenerated expression and activity ratios of the small GTPases Rac and Rho normally found in untransformed MDCK cells. Strikingly, IND 12 treatment decreases the levels of phosphorylated mitogen-activated protein kinases, which are downstream substrates of the Ras-regulated Raf/mitogen-activated protein kinase pathway, and the level of Ras-induced activation of gene expression. Our findings identify a novel drug with high potential in cancer therapy by targeting Ras-induced cell transformation.

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