Effects of arsenic trioxide and hypoxia in multidrug-resistant neuroblastoma

Sammanfattning: Neuroblastoma is a childhood tumour derived from the sympathetic nervous system. Although most children with neuroblastoma initially respond to treatment, approximately 50% of these patients relapse with multidrug-resistant tumours. Arsenic trioxide (As2O3) has been used for centuries to treat different clinical disorders including malignancies. This drug has now attracted new attention since it has been proven efficient for treatment of patients with relapsed acute promyelocytic leukaemia. We have demonstrated that As2O3 is toxic to neuroblastoma cells at clinically relevant concentrations, including cells that are resistant to treatment with cytotoxic drugs commonly used in neuroblastoma therapy. As2O3 is also efficient to cells grown under hypoxic conditions, an import feature since neuroblastoma is a solid tumour with frequent regions of hypoxia. As2O3 - induced cell death does not depend on activation of a classical apoptotic cell death, since inhibition of caspases did not affect the death. However, proteolytic activation of Bax seems to be of importance for As2O3 - induced cell death, since inhibition of Bax cleavage was associated with a reduction in cell death. The cleaved and activated Bax (p18 Bax) was only found in a nuclear fraction in As2O3-treated cells. In order to mimic growth conditions in a solid tumour, neuroblastoma cells were grown at hypoxia in presence or absence of glucose. Growth in absence of glucose induced cell death at normoxia conditions, but growth at hypoxic conditions could inhibit the glucose-deficiency induced cell death. Hypoxic growth conditions seem to rescue the cells through inhibiting glucose-deficiency induced activation of caspases and through induced expression of survival-promoting factors signalling through the MAPK-pathway.