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

Abstract
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.
AuthorsI Ora, L Bondesson, C Jönsson, J Ljungberg, I Pörn-Ares, S Garwicz, S Pâhlman
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 277 Issue 1 Pg. 179-85 (Oct 14 2000) ISSN: 0006-291X [Print] UNITED STATES
PMID11027660 (Publication Type: Journal Article)
CopyrightCopyright 2000 Academic Press.
Chemical References
  • Antigens, Differentiation
  • Antineoplastic Agents
  • Arsenicals
  • Caspase Inhibitors
  • Oxides
  • RNA, Messenger
  • Tetrazolium Salts
  • Thiazoles
  • thiazolyl blue
  • Tretinoin
  • CASP3 protein, human
  • Caspase 3
  • Caspases
  • arsenic trioxide
Topics
  • Antigens, Differentiation
  • Antineoplastic Agents (pharmacology, therapeutic use)
  • Apoptosis (drug effects)
  • Arsenicals (pharmacology, therapeutic use)
  • Caspase 3
  • Caspase Inhibitors
  • Caspases (metabolism)
  • Cell Differentiation (drug effects)
  • Cell Division (drug effects)
  • Cell Survival (drug effects)
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Humans
  • Inhibitory Concentration 50
  • Neoplasm Transplantation
  • Neuroblastoma (drug therapy, metabolism, pathology)
  • Oxides (pharmacology, therapeutic use)
  • RNA, Messenger (genetics, metabolism)
  • Tetrazolium Salts (metabolism)
  • Thiazoles (metabolism)
  • Transplantation, Heterologous
  • Tretinoin (pharmacology)
  • Tumor Cells, Cultured

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