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Arsenic Trioxide-Induced Death of Neuroblastoma Cells Involves Activation of Bax and Does Not Require p53

¹ Divisions of Molecular Medicine and ² Experimental Pathology, Departments of Laboratory Medicine, Malmö, and ³ Pediatrics, Oncology-Hematology Section, Lund University Hospital, Lund, Sweden

Purpose: On the basis of clinical studies showing that arsenic trioxide (As₂O₃), via an apoptotic mechanism, and with minimal toxicity induces complete remission in patients with refractory acute promyelocytic leukemia and that multidrug-resistant and p53-mutated neuroblastoma cells are sensitive to As₂O₃ both in vitro and in vivo, we searched for molecular mechanisms involved in the As₂O₃-induced neuroblastoma cell death.

Experimental Design: We have studied the effect of As₂O₃ on the expression and cellular localization of proteins involved in drug-induced death in two neuroblastoma cell lines with intact p53 and two with mutated p53, the latter two displaying multidrug resistance.

Results: As₂O₃ provoked Bax expression in all tested neuroblastoma cell lines, including SK-N-BE(2) cells with mutated p53 and LA-N-1 cells, which have a deleted p53. In all cell lines exposed to As₂O₃, p21 Bax was proteolytically cleaved in a calpain-dependent way into the more proapoptotic p18 Bax, which was detected exclusively in a mitochondria-enriched subcellular fraction. As₂O₃ also caused an increase of cytoplasmic cytochrome c, translocation of antiapoptosis-inducing factor to the nuclei, and a slight activation of caspase 3. However, inhibition of caspase 3 did not prevent cell death, whereas inhibition of Bax cleavage was associated with a decreased As₂O₃-induced cell death.

Conclusions: We show that multidrug-resistant neuroblastoma cells die after exposure to As₂O₃, independent of functional p53, suggesting activation of a cytotoxic pathway different from that induced by conventional chemotherapeutic agents. We further propose that proteolytic activation of Bax is an important event in As₂O₃-induced cell death.

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