Inhibition of nuclear factor kappa B transcription activity drives a synergistic effect of pyrrolidine dithiocarbamate and cisplatin for treatment of renal cell carcinoma.

Morais, Christudas, Gobe, Glenda, Johnson, David W. and Healy, Helen (2009) Inhibition of nuclear factor kappa B transcription activity drives a synergistic effect of pyrrolidine dithiocarbamate and cisplatin for treatment of renal cell carcinoma.. Apoptosis, 15 4: 412-425. doi:10.1007/s10495-009-0414-y


Author Morais, Christudas
Gobe, Glenda
Johnson, David W.
Healy, Helen
Title Inhibition of nuclear factor kappa B transcription activity drives a synergistic effect of pyrrolidine dithiocarbamate and cisplatin for treatment of renal cell carcinoma.
Journal name Apoptosis   Check publisher's open access policy
ISSN 1360-8185
Publication date 2009-10-24
Sub-type Article (original research)
DOI 10.1007/s10495-009-0414-y
Volume 15
Issue 4
Start page 412
End page 425
Total pages 14
Editor Mels Sluyser
Place of publication United States
Publisher Springer New York
Collection year 2010
Language eng
Subject 1112 Oncology and Carcinogenesis
111201 Cancer Cell Biology
92 Health
C1
Abstract One of the impeding factors in the effective treatment of metastatic renal cell carcinoma (RCC) is their intrinsic and acquired resistance to chemotherapeutics. Many studies have shown that drug resistance, at least in part, is mediated by the upregulation of anti-apoptotic (Bcl-2) and multidrug resistance molecules (MDR-1 and MRP-1) by the transcription factor nuclear factor kappa B (NF-kappaB). Combining NF-kappaB inhibitors with conventional chemotherapeutics could overcome resistance of cancer cells. In this study, we examined the synergistic effect of pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor, and cisplatin, on two human metastatic RCC cell lines ACHN and SN12K1. Individual non-toxic concentrations of PDTC and cisplatin, when combined, synergistically induced a significant increase in apoptosis of the two RCC cell lines. In ACHN cells, the groups with nuclear translocation of NF-kappaB showed resistance to apoptosis, but in SN12K1 cells, the groups with NF-kappaB translocation were susceptible to apoptosis. The combination treatment significantly decreased the transcription activity of all NF-kappaB subunits in both cell lines. Anti-apoptotic proteins Bcl-2 and Bcl-(XL) were significantly decreased in the combination therapy group of both cell lines, but MDR-1 was decreased only in the ACHN cells. No changes in MRP-1 were observed in any of the treatment groups. The results demonstrate the potential of PDTC to be an adjunct therapeutic agent. The major mechanism of the synergistic effect appears to be mediated by the inhibition of transcription activity of NF-kappaB rather than its expression, and the resultant decrease in the anti-apoptotic proteins Bcl-2 and Bcl-(XL).
Keyword Apoptosis
Bcl-2
Bcl-x(l)
Multi-drug Resistance
Nuclear Factor Kappa B
renal cell carcinoma
Q-Index Code C1
Q-Index Status Confirmed Code

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
School of Medicine Publications
 
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Citation counts: TR Web of Science Citation Count  Cited 14 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 20 Apr 2010, 12:11:36 EST by Fiona Mactaggart on behalf of Medicine - Princess Alexandra Hospital