Dual targeting of glioblastoma multiforme with a proteasome inhibitor (Velcade) and a phosphatidylinositol 3-kinase inhibitor (ZSTK474)

Int J Oncol. 2014 Feb;44(2):557-62. doi: 10.3892/ijo.2013.2205. Epub 2013 Dec 2.

Abstract

Proteasome inhibitors have been proven to be effective anticancer compounds in many tumor models, including glioblastoma multiforme (GBM). In this study, we found that the proteasome inhibitor Velcade (PS-341/bortezomib) caused GBM cell death while simultaneously activating the PI3K/Akt pathway. Therefore, we sought to investigate if the PI3K inhibitor ZSTK474 would enhance the effectiveness of Velcade in anticancer therapy. Two GBM cell lines were used to detect the effects of Velcade and ZSTK474 alone or in combination in vitro. The combination of Velcade and ZSTK474 synergistically inhibited the proliferation of GBM cell lines. Cell apoptosis was increased when exposed to Velcade and ZSTK474 in combination as shown by Annexin V analysis. Treatment with both drugs led to downregulation of the p-Akt, p-4EBP1 and p-mTOR proteins as determined by western blot analysis. The anticancer ability of Velcade for glioblastoma multiforme was, therefore, enhanced by combination with the PI3K pathway inhibitor ZSTK474 in glioblastoma multiforme.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols
  • Apoptosis / drug effects*
  • Blotting, Western
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Cell Cycle Proteins
  • Cell Proliferation / drug effects*
  • Drug Synergism
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphoproteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrazines / pharmacology*
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism
  • Triazines / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • Boronic Acids
  • Cell Cycle Proteins
  • EIF4EBP1 protein, human
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins
  • Pyrazines
  • Triazines
  • ZSTK474
  • Bortezomib
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt