Antiproliferative effects of tyrosine kinase inhibitors (tyrphostins) on human bladder and renal carcinoma cells

Abstract

Growth factor receptors with tyrosine kinase activity mediate paracrine and autocrine growth regulation of normal and malignant cells. The epidermal growth factor receptor (EGF-R) is a tyrosine kinase transmembrane protein that is overexpressed by many epithelial malignancies, including transitional cell and renal cell carcinoma. Ligand-induced stimulation of cell growth depends on activation of the tyrosine kinase activity of the EGF-R. Tyrphostins are small molecular weight compounds that have been shown to preferentially inhibit the EGF-R tyrosine kinase and thus may inhibit EGF-R-dependent cell growth. We examined the effect of two tyrphostins, RG14620 and AG555, on the proliferation of three transitional cell carcinoma lines (RT4, J82, and T24) and three renal cell carcinoma lines (A-198, Caki-1, and Caki-2). Both tyrphostins inhibited proliferation of all six cell lines in a dose-dependent fashion. They were equally effective with IC50s ranging between 3 and 16 microM. Complete inhibition of growth was achieved at tyrphostin concentrations between 10 and 30 microM. Although both tyrphostins inhibited proliferation of T24 transitional carcinoma cells in growth assays, only RG14620 but not AG555 was found to specifically inhibit EGF-R autophosphorylation in this cell line. These results suggest that other intracellular targets in addition to the EGF-R are affected by these agents. In summary, tyrphostins are potent growth inhibitors for urological malignancies.