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-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.

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 (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).

RESULTS:

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.

CONCLUSION:

The results demonstrate the potential anti-cancer benefits of treating NF-kappaB positive RCCs with NF-kappaB inhibitors like PDTC.

• Authors: Christudas Morais, Helen Healy, David W Johnson, Glenda Gobe
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 25 Issue 5 Pg. 1462-74 (May 2010) ISSN: 1460-2385 [Electronic] England
• PMID: 20037166 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• Proto-Oncogene Proteins c-bcl-2
• Pyrrolidines
• Thiocarbamates
• bcl-X Protein
• pyrrolidine dithiocarbamic acid
• I-kappa B Kinase

Topics

• Animals
• Apoptosis (drug effects)
• Carcinoma, Renal Cell (drug therapy, pathology)
• Cell Line, Tumor
• Disease Models, Animal
• Disease Progression
• Humans
• I-kappa B Kinase (metabolism)
• Kidney Neoplasms (drug therapy, pathology)
• Male
• Mice
• Mice, SCID
• NF-kappa B (antagonists & inhibitors, genetics)
• Proto-Oncogene Proteins c-bcl-2 (analysis)
• Pyrrolidines (therapeutic use)
• Thiocarbamates (therapeutic use)
• Weight Loss (drug effects)
• Xenograft Model Antitumor Assays
• bcl-X Protein (analysis)