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

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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-κB). Combining NF-κB inhibitors with conventional chemotherapeutics could overcome resistance of cancer cells. In this study, we examined the synergistic effect of pyrrolidine dithiocarbamate (PDTC), a NF-κB 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-κB showed resistance to apoptosis, but in SN12K1 cells, the groups with NF-κB translocation were susceptible to apoptosis. The combination treatment significantly decreased the transcription activity of all NF-κB 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-κB rather than its expression, and the resultant decrease in the anti-apoptotic proteins Bcl-2 and Bcl-XL.

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Acknowledgments

This study was in part supported by the Royal Brisbane and Women’s Hospital Research Foundation and the Queensland Health Pathology and Scientific Service. C.M. is the recipient of a PhD scholarship from the Cancer Council Queensland (formerly Queensland Cancer Fund).

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Authors and Affiliations

  1. Department of Renal Medicine, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia

    Christudas Morais & Helen Healy

  2. Discipline of Medicine, School of Medicine, University of Queensland, Brisbane, QLD, 4029, Australia

    Christudas Morais & Glenda Gobe

  3. Department of Renal Medicine, University of Queensland at Princess Alexandra Hospital, Brisbane, QLD, 4102, Australia

    Glenda Gobe & David W. Johnson

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  1. Christudas Morais
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  2. Glenda Gobe
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Correspondence to Christudas Morais.

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Morais, C., Gobe, G., Johnson, D.W. et al. 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, 412–425 (2010). https://doi.org/10.1007/s10495-009-0414-y

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