213Bi-induced death of HSC45-M2 gastric cancer cells is characterized by G2 arrest and up-regulation of genes known to prevent apoptosis but induce necrosis and mitotic catastrophe

Mol Cancer Ther. 2007 Aug;6(8):2346-59. doi: 10.1158/1535-7163.MCT-07-0132.

Abstract

Tumor cells are efficiently killed after incubation with alpha-emitter immunoconjugates targeting tumor-specific antigens. Therefore, application of alpha-emitter immunoconjugates is a promising therapeutic option for treatment of carcinomas that are characterized by dissemination of single tumor cells in the peritoneum like ovarian cancer or gastric cancer. In diffuse-type gastric cancer, 10% of patients express mutant d9-E-cadherin on the surface of tumor cells that is targeted by the monoclonal antibody d9MAb. Coupling of the alpha-emitter (213)Bi to d9MAb provides an efficient tool to eliminate HSC45-M2 gastric cancer cells expressing d9-E-cadherin in vitro and in vivo. Elucidation of the molecular mechanisms triggered by alpha-emitters in tumor cells could help to improve strategies of alpha-emitter radioimmunotherapy. For that purpose, gene expression of (213)Bi-treated tumor cells was quantified using a real time quantitative-PCR low-density array covering 380 genes in combination with analysis of cell proliferation and the mode of cell death. We could show that (213)Bi-induced cell death was initiated by G(2) arrest; up-regulation of tumor necrosis factor (TNF), SPHK1, STAT5A, p21, MYT1, and SSTR3; and down-regulation of SPP1, CDC25 phosphatases, and of genes involved in chromosome segregation. Together with morphologic changes, these results suggest that (213)Bi activates death cascades different from apoptosis. Furthermore, (213)Bi-triggered up-regulation of SSTR3 could be exploited for improvement of the therapeutic regimen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis / radiation effects
  • Bismuth / pharmacology*
  • Cell Line, Tumor
  • Chromosome Segregation / drug effects
  • Chromosome Segregation / radiation effects
  • Chromosomes, Human / metabolism
  • DNA Repair / drug effects
  • DNA Repair / radiation effects
  • Down-Regulation / drug effects
  • Down-Regulation / radiation effects
  • G2 Phase / drug effects*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Genes, Neoplasm*
  • Humans
  • Mitosis / drug effects
  • Mitosis / radiation effects
  • Necrosis / pathology
  • Oligonucleotide Array Sequence Analysis
  • Radioisotopes / pharmacology*
  • S Phase / drug effects
  • S Phase / radiation effects
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology
  • Tumor Necrosis Factors / genetics
  • Up-Regulation / drug effects*
  • Up-Regulation / radiation effects

Substances

  • Antibodies, Monoclonal
  • Radioisotopes
  • Tumor Necrosis Factors
  • Bismuth