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.
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.
Seidl
Christof
C
Department of Nuclear Medicine, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany. Christof.Seidl@lrz.tum.de
Port
Matthias
M
Gilbertz
Klaus-Peter
KP
Morgenstern
Alfred
A
Bruchertseifer
Frank
F
Schwaiger
Markus
M
Röper
Barbara
B
Senekowitsch-Schmidtke
Reingard
R
Abend
Michael
M
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D001729:Bismuth / Q000494:pharmacology*; D045744:Cell Line, Tumor; D020090:Chromosome Segregation / Q000187:drug effects / Q000528:radiation effects; D002877:Chromosomes, Human / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D015536:Down-Regulation / Q000187:drug effects / Q000528:radiation effects; D016195:G2 Phase / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000528:radiation effects; D052138:Genes, Neoplasm; D006801:Humans; D008938:Mitosis / Q000187:drug effects / Q000528:radiation effects; D009336:Necrosis / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011868:Radioisotopes / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects / Q000528:radiation effects; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D048069:Tumor Necrosis Factors / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects* / Q000528:radiation effects
D000911:Antibodies, Monoclonal; D011868:Radioisotopes; D048069:Tumor Necrosis Factors; D001729:Bismuth