Sensitizing Nanosomal TRAIL Response By The Chemo Drug AZD5582 In Neuroblastoma

Neuroblastoma is a metastatic brain tumor particularly common in children.The cure rate is below 50% for patients of high-risk condition.Novel therapeutic agents and approaches are needed to improve the cure rate.Tumor necrosis factor-related and apoptosisinducing ligand（TRAIL）is a promising proapoptotic factor that rapidly induces apoptosis preferentially in transformed and cancerous cells.Unfortunately,the common TRAIL resistance in cancers has hampered the clinical application of the ligand.Previously we prepared a novel TRAIL armed ER derived nanosomal agent（ERN-T）that overcomes TRAIL resistance in some cancer lines when combined with a synthetic antagonist of inhibitors of apoptosis proteins（IAPs）,AZD5582.However,how AZD5582 sensitizes cancer cells to ERN-T remains not well understood.In this study we continued to test the therapeutic efficacy of the combinatory therapy of ERN-T and AZD5582 on neuroblastoma,aiming to reveal the molecular mechanism underlying the synergism between AZD5582 and ERN-T.The obtained data revealed that ERN-Ts overcame TRAIL resistance and showed significant cytotoxicity on the resistant neuroblastoma line SH-SH5 Y when combined with AZD5582 whilst sparing normal cells.The combination of low doses of ERN-Ts and AZD5582 induced intensive apoptosis in SH-SY5 Y but not in normal skin fibroblasts（NSFs）.Importantly we discovered that TRAIL sensitization in SH-SY5 Y was associated with the concomitant downregulation of antiapoptotic factors cFLIP,MCL-1 and IAPs and upregulation of proapoptotic protein BAX and the death receptor 5（DR5）by the cotreatment of ERN-T and AZD5582.In vivo study demonstrated that the combination of ERN-T and AZD5582 constituted a highly effective and safe therapy for subcutaneous SH-SY5 Y xenograft neuroblastoma in nude mice.In conclusion,we identified that the concomitant regulation of both antiapoptotic and proapoptotic factors and DR5 is an essential molecular mechanism for overcoming TRAIL resistance in SH-SY5 Y and the combination of ERN-T and AZD5582 potentially constitutes a novel therapeutic strategy,which is highly effective and safe for neuroblastoma.