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

Abstract

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-kappaB) 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-kappaB inhibitor, in a murine xenograft model of RCC. 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 (50 mg/kg) on RCC growth analysed 5 weeks later. The analyses carried out in three groups (no treatment, RCC alone and RCC + PDTC) at 5 weeks were: renal weight, protein expression by immunohistochemistry and Western immunoblot, apoptosis (TdT-mediated nick end labelling and morphology) and mitosis (morphology). PDTC significantly decreased RCC growth and the expression of NF-kappaB subunits (p50, p52, c-Rel and RelB), upstream IKK-beta and IKK-gamma, but did not induce any changes in the expression of IkappaB-alpha and IkappaB-beta. 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. The results demonstrate the potential anti-cancer benefits of treating NF-kappaB positive RCCs with NF-kappaB inhibitors like PDTC.