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Arsenic trioxide inhibits neuroblastoma growth in vivo and promotes apoptotic cell death in vitro

Author:
  • Ingrid Øra
  • Lennart Bondesson
  • Carolin Jönsson
  • June Ljungberg
  • Isabella Ares
  • Stanislaw Garwicz
  • Sven Påhlman
Publishing year: 2000
Language: English
Pages: 179-185
Publication/Series: Biochemical and Biophysical Research Communications
Volume: 277
Issue: 1
Document type: Journal article
Publisher: Elsevier

Abstract english

Recent clinical studies have shown that inorganic arsenic trioxide (As(2)O(3)) at low concentrations induces complete remission with minimal toxicity in patients with refractory acute promyelocytic leukemia (APL). Preclinical studies suggest that As(2)O(3) induces apoptosis and possibly differentiation in APL cells. Like APL cells, neuroblastoma (NB) cells are thought to be arrested at an early stage of differentiation, and cells of highly malignant tumors fail to undergo spontaneous maturation. Both APL and NB cells can respond with differentiation to retinoic acid (RA) treatment in vitro and probably also in vivo. For that reason we investigated the effect of As(2)O(3) alone and in combination with RA on NB cell lines. In vitro, the number of viable NB cells was reduced at As(2)O(3) concentrations around 1 microM after 72 h exposure. The IC50 in six different cell lines treated for 3 days was in the 1.5 to 5 microM concentration interval, the most sensitive being SK-N-BE(2) cells derived from a chemotherapy resistant tumor. The combined treatment with RA (1 and 3 microM) showed no consistent additional effect with regard to induced cell death. The effect of As(2)O(3) on NB cell number involved As(2)O(3)-induced apoptotic pathways (decreased expression of Bcl-2 and stimulation of caspase-3 activity) with no clear evidence of induced differentiation. The in vivo effect of As(2)O(3) on NB growth was also investigated in nude mice bearing tumors of xenografted NB cells. Although tumor growth was reduced by As(2)O(3) treatment, complete remission was not achieved at the concentrations tested. We suggest that As(2)O(3), in combination with existing treatment modalities, might be a treatment approach for high risk NB patients.

Keywords

  • Biological Sciences
  • animal tumor model
  • apoptosis
  • arsenic trioxide
  • differentiation
  • neuroblastoma

Other

Published
  • Diabetes and Endocrinology
  • Experimental Pathology, Malmö
  • ISSN: 1090-2104
Sven Påhlman
E-mail: sven [dot] pahlman [at] med [dot] lu [dot] se

Professor

Division of Translational Cancer Research

+46 46 222 64 21

MV406 312K1

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