Inhibition of nuclear factor kappa B attenuates tumour progression in an animal model of renal cell carcinoma

Abstract

Background. Renal cell carcinoma (RCC) is a highly metastatic and lethal disease with few efficacious treatments. Many studies have shown that the ubiquitous transcription factor nuclear factor kappa B (NF-κB) plays a key role in the development and progression of many cancers including RCC. The aim of this investigation was to evaluate the anti-cancer effect of pyrrolidine dithiocarbamate (PDTC), a NF-κB inhibitor, in a murine xenograft model of RCC.Methods. The metastatic human RCC cell line, SN12K1, was inoculated into the left kidneys of severe combined immunodeficiency mice and the effect of semi-continuous PDTC treatment (50mg/kg) on RCC growth analysed 5 weeks later. The analyses carried out in three groups (no treatment, RCC alone and RCC+PDTC) at 5weeks were: renal weight, protein expression by immunohistochemistry and Western immunoblot, apoptosis (TdT-mediated nick end labelling and morphology) and mitosis (morphology).Results. PDTC significantly decreased RCC growth and the expression of NF-κB subunits (p50, p52, c-Rel and RelB), upstream IKK-β and IKK-γ, but did not induce any changes in the expression of IκB-α and IκB-β. RCC growth was associated with a significant decrease in the expression of the anti-apoptotic proteins Bcl-2 and Bcl-XL and increase in pro-apoptotic Bax, all of which were reversed by PDTC. Cell proliferation was significantly reduced by PDTC.Conclusion. The results demonstrate the potential anti-cancer benefits of treating NF-κB positive RCCs with NF-κB inhibitors like PDTC. © The Author 2009. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.