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


CONCLUSIONS
The results demonstrate the potential anti-cancer benefits of treating NF-kappaB positive RCCs with NF-kappaB inhibitors like PDTC.
Morais
Christudas
C
Department of Renal Medicine, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia. c.morais@uq.edu.au
Healy
Helen
H
Johnson
David W
DW
Gobe
Glenda
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011759:Pyrrolidines / Q000627:therapeutic use*; D013859:Thiocarbamates / Q000627:therapeutic use*; D015431:Weight Loss / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000032:analysis
D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011759:Pyrrolidines; D013859:Thiocarbamates; D051020:bcl-X Protein; C020972:pyrrolidine dithiocarbamic acid; D051550:I-kappa B Kinase