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Downregulation of Bcl-2 sensitises interferon-resistant renal cancer cells to Fas

J D Kelly1, J Dai, P Eschwege

  • 1Department of Oncology, Cambridge University, Box 193, Addenbrookes Hospital, Cambridge CB2 2QQ, UK. jk334@cam.ac.uk

British Journal of Cancer
|June 10, 2004
PubMed

Insights

Interferon alpha (IFNalpha) shows limited benefit for advanced renal cell carcinoma (RCC). Combining IFNalpha with G3139, an antisense compound targeting Bcl-2, may enhance cancer cell death via Fas-mediated pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Interferon alpha (IFNalpha) is a treatment for advanced renal cell carcinoma (RCC) with limited efficacy.
  • IFNalpha can induce apoptosis through Fas receptor and caspase activation, but Bcl-2 family proteins can inhibit this process.
  • Understanding these pathways is crucial for developing more effective RCC therapies.

Purpose of the Study:

  • To investigate the efficacy of G3139, an antisense compound targeting Bcl-2, in combination with IFNalpha for treating renal cell carcinoma.
  • To explore the mechanisms of cell death induced by IFNalpha and G3139 in RCC cell lines.

Main Methods:

  • Human RCC cell lines (SK-RC-44 and SK-RC-07) were treated with IFNalpha and/or G3139.
  • Fas-mediated cytotoxicity was induced using anti-Fas mAb (CH11).
  • Expression levels of Bcl-2 and Fas, and PARP cleavage were analyzed.

Main Results:

  • IFNalpha upregulated Fas and Bcl-2 in both RCC cell lines.
  • IFNalpha sensitized SK-RC-44 cells to anti-Fas, leading to PARP cleavage and demonstrating a cytotoxic effect.
  • G3139 downregulated Bcl-2 in SK-RC-07 cells, sensitizing them to anti-Fas when combined with IFNalpha.

Conclusions:

  • Renal cell carcinoma exhibits both Fas-dependent and alternative cell death pathways that can be inhibited by Bcl-2.
  • The combination of G3139 and IFNalpha shows potential as a therapeutic strategy for metastatic renal cell carcinoma.

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