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.