Synergistic effects of topoisomerase I inhibitor, SN38, on Fas-mediated apoptosis

Anticancer Res. 2010 Oct;30(10):3911-7.

Abstract

Inhibitors of topoisomerase I, such as camptothecin, have proven to be among the most promising new classes of anti-neoplastic agents introduced into the clinical setting in recent years. Irinotecan (CPT-11) is one of the most widely used camptothecin analogs and is converted to form the active metabolite SN-38. The present study was designed to explore apoptosis induced by SN38 and anti-Fas antibody (CH11) in WR/Fas-SMS1 cells and its possible mechanisms. The results demonstrate that combination of SN38 and CH11 synergistically enhanced cell apoptosis in WR/Fas-SMS1 cells. Western blotting analysis showed that combination of SN38 and CH11 activated the ATM-Chk1-p53 pathway, increased protein expression of phospho-p53 and cleavaged caspase-3, but down-regulated expression of phospho-p21. Our data suggest that combination of SN38 and CH11 enhanced apoptosis through down-regulation of p21 phosphorylation. In conclusion, inhibition of p21 could be a new adjuvant approach in cancer therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • Apoptosis / drug effects
  • Ataxia Telangiectasia Mutated Proteins
  • Camptothecin / analogs & derivatives*
  • Camptothecin / pharmacology
  • Caspase 3 / metabolism
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Checkpoint Kinase 1
  • DNA-Binding Proteins / metabolism
  • Drug Synergism
  • Enzyme Activation / drug effects
  • Humans
  • Irinotecan
  • Lymphoma, T-Cell / drug therapy
  • Lymphoma, T-Cell / enzymology
  • Lymphoma, T-Cell / immunology
  • Lymphoma, T-Cell / pathology
  • Mice
  • Protein Kinases / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Topoisomerase I Inhibitors / pharmacology*
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / metabolism
  • fas Receptor / genetics
  • fas Receptor / immunology*

Substances

  • Antibodies, Monoclonal
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Topoisomerase I Inhibitors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • fas Receptor
  • Irinotecan
  • Protein Kinases
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • CHEK1 protein, human
  • Checkpoint Kinase 1
  • Chek1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Caspase 3
  • Camptothecin