aee-788 and Kidney-Neoplasms

To evaluate adhesion and growth inhibiting effects of the multiple receptor tyrosine kinase inhibitor AEE788 and the histone deacetylase (HDAC) inhibitor valproic acid (VPA) on renal cell carcinoma (RCC) cells.. Caki-1 cells were treated with AEE788 and VPA, either alone or in combination, to investigate RCC cell adhesion to vascular endothelial cells or to immobilized extracellular matrix proteins. Tumour cell proliferation was examined by MTT dye reduction assay. Effects of drug treatment on cell signalling pathways were determined by Western blotting. The expression levels of integrin alpha and beta subtypes were evaluated by flow cytometry (surface expression) and Western blotting (intracellular protein expression).. RCC cell treatment with AEE788 and VPA in combination resulted in a stronger inhibition of tumour cell proliferation than that caused by either drug alone. There were also additive effects of the combined treatment on tumour cell adhesion to endothelial cells and to immobilized laminin (but not to immobilized fibronectin and collagen). AEE788 alone or combined with VPA reduced Akt expression and histone H3 acetylation. Both compounds altered integrin alpha and beta subtype expression, in particular alpha1, alpha3 and beta4, and blocked integrin-dependent integrin-linked kinase and focal-adhesion kinase (total and phosphorylated) signalling.. Both AEE788 and VPA profoundly block the interaction of RCC cells with endothelium and extracellular matrix and reduce tumour growth in vitro. Therefore, this combined regimen warrants further preclinical and possible clinical study for treating advanced RCC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blotting, Western; Carcinoma, Renal Cell; Cell Adhesion; Cell Line, Tumor; Drug Screening Assays, Antitumor; Endothelium, Vascular; Extracellular Matrix Proteins; Flow Cytometry; Humans; Integrin alpha Chains; Integrin beta Chains; Kidney Neoplasms; Purines; Valproic Acid

Conventional therapeutic approaches to treat advanced renal cell carcinoma (RCC) are of limited benefit. Receptor tyrosine kinase inhibitors (RTKI) may open up novel treatment options. In the present study, the effects of the RTKI AEE788 on the growth and adhesion capacity of RCC cell lines were evaluated in vitro.. RCC cells were treated with AEE788, and alterations of tumor growth and tumor cell interaction with vascular endothelium or extracellular matrix proteins were analyzed. Furthermore, the addition of interferon alpha (IFNalpha) was investigated to see whether it may enhance the anti-tumoral potential of AEE788.. AEE788 significantly blocked RCC cell growth and adhesion. Analysis of alpha- and beta-integrins revealed distinct alterations of the receptor expression profile and downregulation of integrin-dependent signaling. Growth-blocking effects were further enhanced when the AEE788-IFNalpha combination protocol was applied. In addition, downregulation of integrin-dependent signaling was more intense in the presence of a combination of AEE788 and IFNalpha than with AEE788 monotherapy.. AEE788 exerts significant anti-tumoral properties, particularly when combined with IFNalpha. AEE788 may therefore be an encouraging compound to treat advanced RCC.

Topics: Carcinoma, Renal Cell; Cell Adhesion; Cell Division; Cell Line, Tumor; Dose-Response Relationship, Drug; Down-Regulation; Drug Evaluation, Preclinical; Drug Synergism; ErbB Receptors; Humans; In Vitro Techniques; Integrin alpha Chains; Integrin beta Chains; Interferon alpha-2; Interferon-alpha; Kidney Neoplasms; Purines; Receptors, Vascular Endothelial Growth Factor; Recombinant Proteins; Signal Transduction