OSU-03012 in the treatment of glioblastoma.

Abstract

In an article presented in this issue of Molecular Pharmacology, Yacoub et al. (p. 589) examine the actions of 2-amino-N{4-5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-acetamide (OSU-03012) on both primary and glioblastoma cell lines. The authors found that OSU-03012 could induce tumor cell death by itself but also acted as a strong sensitizing agent to radiotherapy-induced cell death. Glioblastoma cells were also more sensitive to this compound than nontransformed astrocytes. Radiation-induced cell death was refractory to small interfering RNA-directed inhibition of PDK1 but not OSU-03012. These results indicate that OSU-03012, which has been thought to primarily mediate antitumor effects via the inhibition of PDK1, has actions independent of PDK1. Furthermore, the authors demonstrated that the effects of OSU-03012 were independent of ERB-B1-vIII and PTEN expression. These are important findings because they start to identify a new mechanism to sensitize glioblastoma cells and also suggest that OSU-03012 could be combined with existing inhibitors to further sensitize tumor cells. In glioblastoma cells, OSU-03012 seemed to induce apoptosis via endoplasmic reticulum stress-induced PERK-dependent signaling. OSU-03012-induced death of the glioblastoma was only weakly suppressed by the pan-caspase inhibitor, N-benzyloxycarbonyl-Val-Ala-Asp, suggesting that OSU-03012-induced cell death was largely caspase-independent. Overall, these are exciting results and suggest that new more effective treatment options may be obtainable for people suffering from these deadly tumors.

• Authors: James A McCubrey, Michelle M Lahair, Richard A Franklin
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 70 Issue 2 Pg. 437-9 (Aug 2006) ISSN: 0026-895X [Print] United States
• PMID: 16675657 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• OSU 03012
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Pyrazoles
• Sulfonamides
• 3-Phosphoinositide-Dependent Protein Kinases
• PDPK1 protein, human
• PERK kinase
• Protein Serine-Threonine Kinases
• eIF-2 Kinase
• Extracellular Signal-Regulated MAP Kinases

Topics

• 3-Phosphoinositide-Dependent Protein Kinases
• Brain Neoplasms (drug therapy)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors)
• Glioblastoma (drug therapy)
• Humans
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (therapeutic use)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Pyrazoles (therapeutic use)
• Sulfonamides (therapeutic use)
• eIF-2 Kinase (physiology)