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OSU-03012 in the Treatment of Glioblastoma

James A. McCubrey, Michelle M. LaHair and Richard A. Franklin
Molecular Pharmacology August 2006, 70 (2) 437-439; DOI: https://doi.org/10.1124/mol.106.026252
James A. McCubrey
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Michelle M. LaHair
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Richard A. Franklin
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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.

  • Received May 2, 2006.
  • Accepted May 4, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 70 (2)
Molecular Pharmacology
Vol. 70, Issue 2
1 Aug 2006
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OSU-03012 in the Treatment of Glioblastoma

James A. McCubrey, Michelle M. LaHair and Richard A. Franklin
Molecular Pharmacology August 1, 2006, 70 (2) 437-439; DOI: https://doi.org/10.1124/mol.106.026252

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OSU-03012 in the Treatment of Glioblastoma

James A. McCubrey, Michelle M. LaHair and Richard A. Franklin
Molecular Pharmacology August 1, 2006, 70 (2) 437-439; DOI: https://doi.org/10.1124/mol.106.026252
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