The novel Bcl-2 inhibitor ABT-737 is more effective in hypoxia and is able to reverse hypoxia-induced drug resistance in neuroblastoma cells

摘要

Neuroblastoma is a common solid tumour of childhood and advanced disease carries a poor prognosis despite intensive multi-modality therapy. Hypoxia is a common feature of solid tumours due to poorly organised tumour-induced neovasculature. Hypoxia is associated with advanced stage and poor outcome in a range of tumour types, and leads to resistance to clinically relevant cytotoxic agents in neuroblastoma and other paediatric tumours in vitro. Resistance to apoptosis is a common feature of tumour cells, and leads to pleiotropic drug resistance, mediated by Bcl-2 family proteins. ABT-737 is a novel small molecule inhibitor of Bcl-2 and Bcl-xL that is able to induce apoptosis in a range of tumour types. Neuroblastoma cell lines are relatively resistant to ABT-737-induced apoptosis in normoxia, but in contrast to the situation with conventional cytotoxic agents, are more sensitive in hypoxia. This sensitisation is due to an increase in ABT-737-induced apoptosis and is variably dependent upon the presence of functional HIF-1α. In contrast to the situation in colon carcinoma and non small cell lung cancer cells hypoxia does not result in down-regulation of the known ABT-737 resistance factor, Mcl-1, nor any other Bcl-2 family proteins. ABT-737 sensitises neuroblastoma cells to clinically relevant cytotoxic agents under normal levels of oxygen, and importantly this sensitisation is maintained under hypoxia, when neuroblastoma cells are resistant to these agents. Thus rational combinations of ABT-737 and conventional cytotoxics offer a novel approach to overcoming hypoxia-induced drug resistance in neuroblastoma.