POSTTRANSCRIPTIONAL UPREGULATION OF XIAP EXPRESSION AND EFFECT OF XIAP INHIBITION IN NEUROBLASTOMA

Purpose: Neuroblastoma is the most common extracranial solid tumor during infancy and childhood and more than 50% of the patients initially present with disseminated stage IV disease. Despite intensive therapy including high-dose chemotherapy and autologous stem cell rescue outcome for stage IV patients is still poor. X-linked inhibitor of apoptosis (XIAP) is a major intrinsic cellular suppressor of apoptosis and XIAP overexpression has been shown in several malignancies. XIAP inhibition by SMAC mimetics represents a novel innovative treatment strategy for refractory malignant disease. Method: In this study, XIAP protein and mRNA expression was determined in human and murine neuroblastoma cell lines as well as primary patients samples. Combination of chemotherapy and XIAP inhibition by SMAC mimetics was tested for induction of
apoptosis neuroblastoma cell lines. Results: High XIAP protein expression was detected in all neuroblastoma cell lines and primary patient samples. XIAP protein expression was highly increased in murine neuroblastoma compared to normal adrenal gland tissue. In contrast, XIAP mRNA expression was similar in all investigated tissues indicating a posttranscriptional mechanism of XIAP regulation. XIAP inhibition by SMAC mimetics significantly increased induction of apoptosis by vincristine and etoposide in a murine neuroblastoma cell culture model. Conclusion: Posttranscriptional regulation of XIAP expression results in high XIAP protein expression in neuroblastoma cells. XIAP inhibition by SMAC mimetics appears to be a promising novel approach for treatment of neuroblastoma.