alexa Arsenic trioxide-induced death of neuroblastoma cells involves activation of Bax and does not require p53.


Journal of Cancer Science & Therapy

Author(s): Karlsson J, ra I, PrnAres I, Phlman S

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Abstract PURPOSE: On the basis of clinical studies showing that arsenic trioxide (As(2)O(3)), 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 As(2)O(3) both in vitro and in vivo, we searched for molecular mechanisms involved in the As(2)O(3)-induced neuroblastoma cell death. EXPERIMENTAL DESIGN: We have studied the effect of As(2)O(3) 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: As(2)O(3) 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 As(2)O(3), 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. As(2)O(3) 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 As(2)O(3)-induced cell death. CONCLUSIONS: We show that multidrug-resistant neuroblastoma cells die after exposure to As(2)O(3), 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 As(2)O(3)-induced cell death.
This article was published in Clin Cancer Res and referenced in Journal of Cancer Science & Therapy

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