NF-kappaB inhibition restores sensitivity to Fas-mediated apoptosis in lymphoma cell lines

Ann N Y Acad Sci. 2003 Dec;1010:232-6. doi: 10.1196/annals.1299.041.

Abstract

Failure to perform the Fas-related apoptosis pathway can account for tumor resistance both to chemotherapeutic agents and to immunological effectors. We studied the role of NK-kappaB in Fas-resistance, employing the Fas-sensitive human T-lymphoma HuT78 cell line and its Fas-resistant variants HuT78B1 and HuT78G9. All these cell lines expressed high levels of constitutively activated NF-kappaB. Pretreatment of cells with NF-kappaB inhibitors (PDTC, MG132, or SN50) strongly enhanced CH11-induced apoptosis in HuT78 and Hut78G9 cells, while only MG132 showed a similar potentiating effect in HuT78B1. The described synergism was significantly inhibited by pretreatment with the anti-Fas-blocking antibody ZB4 or with the pancapsase inhibitor Z-VAD-FMK, but not by capsase-8 or -9 inhibitors. Overall, these data suggest that NF-kappaB inhibition may restore the Fas-pathway in Fas-resistant NF-kappaB-overexpressing tumors.

MeSH terms

  • Antineoplastic Agents / toxicity*
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Cell Line, Tumor
  • Humans
  • Leupeptins / toxicity*
  • Lymphoma, T-Cell
  • NF-kappa B / antagonists & inhibitors*
  • Peptides / toxicity
  • Proline / analogs & derivatives*
  • Proline / toxicity*
  • Thiocarbamates / toxicity*
  • fas Receptor / physiology*

Substances

  • Antineoplastic Agents
  • Leupeptins
  • NF-kappa B
  • Peptides
  • SN50 peptide
  • Thiocarbamates
  • fas Receptor
  • prolinedithiocarbamate
  • Proline
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde