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

Øra, Ingrid LU ; Bondesson, Lennart; Jönsson, Carolin LU ; Ljungberg, June LU ; Ares, Isabella LU ; Garwicz, Stanislaw LU and Påhlman, Sven LU (2000) In Biochemical and Biophysical Research Communications 277(1). p.179-185
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
animal tumor model, apoptosis, arsenic trioxide, differentiation, neuroblastoma
in
Biochemical and Biophysical Research Communications
volume
277
issue
1
pages
179 - 185
publisher
Elsevier
external identifiers
  • pmid:11027660
  • scopus:0034649163
ISSN
1090-2104
DOI
10.1006/bbrc.2000.3651
language
English
LU publication?
yes
id
437e6f3c-3cc8-48ef-86e6-5f53ab5bf7c3 (old id 1116248)
date added to LUP
2008-07-01 10:55:42
date last changed
2017-01-01 07:11:11
@article{437e6f3c-3cc8-48ef-86e6-5f53ab5bf7c3,
  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.},
  author       = {Øra, Ingrid and Bondesson, Lennart and Jönsson, Carolin and Ljungberg, June and Ares, Isabella and Garwicz, Stanislaw and Påhlman, Sven},
  issn         = {1090-2104},
  keyword      = {animal tumor model,apoptosis,arsenic trioxide,differentiation,neuroblastoma},
  language     = {eng},
  number       = {1},
  pages        = {179--185},
  publisher    = {Elsevier},
  series       = {Biochemical and Biophysical Research Communications},
  title        = {Arsenic trioxide inhibits neuroblastoma growth in vivo and promotes apoptotic cell death in vitro},
  url          = {http://dx.doi.org/10.1006/bbrc.2000.3651},
  volume       = {277},
  year         = {2000},
}