Improved cancer survival rates can be achieved by strategies that specifically target tumor-cell resistance to apoptosis, but the precise cellular mechanisms that control this process have been unclear. In 15 July advanced online Nature Medicine, Simone Fulda and colleagues at the University Children's Hospital, Ulm, Germany, show that transfer of the gene encoding second mitochondria-derived activator of caspase (Smac) or Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo (Nat Med 2002, DOI:10.1038/nm735).

Fulda et al. observed that expression of a cytosolic active form of Smac or Smac peptides could sensitize resistant neuroblastoma or melanoma cells and patient-derived primary neuroblastoma cells ex vivo. In addition, Smac peptides strongly enhanced the antitumor activity of Apo-2L/tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in an intracranial malignant glioma xenograft model in vivo. Combined treatment with Smac peptides and Apo2L/TRAIL achieved complete...

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