Inhibition of Akt survival pathway by a small-molecule inhibitor in human glioblastoma

Mol Cancer Ther. 2006 Mar;5(3):637-44. doi: 10.1158/1535-7163.MCT-05-0453.


Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and Akt are important regulators of the phosphatidylinositol 3-kinase (PI3K) pathway and thus are important to the regulation of a wide spectrum of tumor-related biological processes. Akt regulates several critical cellular functions, including cell cycle progression; cell migration, invasion, and survival; and angiogenesis. Decreased expression of PTEN and overexpression of the Akt proto-oncogene, which is located downstream of PI3K, have been shown in a variety of cancers, including glioblastoma. Novel small-molecule inhibitors of receptors and signaling pathways, including inhibitors of the PI3K pathway, have shown antitumor activity, but inhibitors of Akt have not been examined. In this study, we tested our hypothesis that the pharmacologic inhibition of Akt has an antiproliferative effect on gliomas. We showed that two newly developed Akt inhibitors, KP-372-1 and KP-372-2 (herein called KP-1 and KP-2), effectively inhibited the PI3K/Akt signaling cascade. KP-1 and KP-2 blocked both the basal and epidermal growth factor-induced phosphorylation of Akt Ser473 at 125 and 250 nmol/L, which, in turn, reduced the activation of intracellular downstream targets of Akt, including GSK-3beta and p70s6k. Furthermore, the treatment of U87 and U251 glioma cells with 125 to 250 nmol/L KP-1 and KP2 for 48 hours inhibited cell growth by approximately 50%. This decrease in cell growth stemmed from the induction of apoptosis. Collectively, these results provide a strong rationale for the pharmacologic targeting of Akt for the treatment of gliomas.

Publication types

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

MeSH terms

  • Apoptosis Regulatory Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Central Nervous System Neoplasms / enzymology*
  • Enzyme Activation / drug effects
  • Epidermal Growth Factor / antagonists & inhibitors
  • Glioblastoma / enzymology*
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Humans
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Serine / metabolism
  • Signal Transduction
  • Tetrazoles / pharmacology*


  • Apoptosis Regulatory Proteins
  • Heterocyclic Compounds, 4 or More Rings
  • KP372-1
  • Tetrazoles
  • Serine
  • Epidermal Growth Factor
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Glycogen Synthase Kinase 3