Tumor therapy mediated by lentiviral expression of shBcl-2 and S-TRAIL

Neoplasia. 2007 May;9(5):435-42. doi: 10.1593/neo.07223.


Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively kill tumor cells and, in combination with other agents, could enhance tumor therapy. We explored the combined therapeutic effects of a secretable form of (S) TRAIL-induced apoptosis and the downregulation of Bcl-2 in human gliomas. We constructed a lentiviral delivery system: 1) for the expression of short hairpin (sh) RNA to downregulate Bcl-2 and for the expression of S-TRAIL to induce apoptosis in glioma cells; and 2) to follow delivery in vitro and the fate of tumors in real time in vivo. We demonstrate that lentiviral-mediated simultaneous downregulation of Bcl-2 and S-TRAIL-induced apoptosis leads to an increased expression of activated caspase-3 and caspase-7, thus resulting in accelerated S-TRAIL-mediated apoptosis in glioma cells in vitro. Using a highly malignant human glioma model expressing EGFRvIII and firefly luciferase, we show that the combined effect of Bcl-2 downregulation and S-TRAIL-induced apoptosis results in complete eradication of gliomas compared to S-TRAIL monotherapy. These results show that simultaneous triggering of TRAIL-mediated death receptor pathway and downregulation of Bcl-2 by shRNA leads to enhanced eradication of gliomas and serves as a template in developing and monitoring combination therapies for the treatment of drug-resistant cancers.

MeSH terms

  • Animals
  • Apoptosis*
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cell Line, Tumor
  • Down-Regulation
  • Genetic Therapy
  • Genetic Vectors
  • Glioma / pathology
  • Glioma / therapy*
  • Lentivirus / genetics*
  • Mice
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • RNA Interference
  • TNF-Related Apoptosis-Inducing Ligand / genetics*


  • Proto-Oncogene Proteins c-bcl-2
  • TNF-Related Apoptosis-Inducing Ligand
  • Caspase 3
  • Caspase 7