Combination therapy using Notch and Akt inhibitors is effective for suppressing invasion but not proliferation in glioma cells.

Abstract

Molecular targeted therapy can potentially provide more effective treatment for patients with high-grade gliomas. Notch and Akt are notable target molecules as they play important roles in a variety of cellular processes, such as regeneration, differentiation, proliferation, migration, and invasion. Here, we assessed the therapeutic possibility of inhibiting Notch and Akt in gliomas using the clinically available, selective small molecule inhibitors MRK003 and MK-2206. We evaluated their efficacy individually and as a combination therapy in U251 and U87 glioma cell lines. We confirmed that MK-2206 effectively inhibits Akt phosphorylation in a dose-dependent manner, whereas MRK003 inhibits Notch signaling and Akt phosphorylation. Both MRK003 and MK-2206 significantly inhibited cell growth, migration, and invasion in a dose-dependent manner. Akt dephosphorylation was enhanced by combination therapy with MRK003 and MK-2206. However, the effect of combination treatment did not exceed that of MK-2206 monotherapy in proliferation assay. Inhibition of invasion, further enhanced by combination therapy, correlated with increased Akt inactivation. In summary, combination therapy with MRK003 and MK-2206 may be effective for inhibiting invasion but not proliferation.

• Authors: Rihua Jin, Mitsutoshi Nakada, Lei Teng, Takuya Furuta, Hemragul Sabit, Yutaka Hayashi, Tim Demuth, Atsushi Hirao, Hiroshi Sato, Gang Zhao, Jun-Ichiro Hamada
• Journal: Neuroscience letters (Neurosci Lett) Vol. 534 Pg. 316-21 (Feb 08 2013) ISSN: 1872-7972 [Electronic] Ireland
• PMID: 23262078 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cyclic S-Oxides
• Heterocyclic Compounds, 3-Ring
• MK 2206
• MRK 003
• Receptors, Notch
• Thiadiazoles
• Proto-Oncogene Proteins c-akt

Topics

• Antineoplastic Agents (pharmacology)
• Brain Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cyclic S-Oxides (pharmacology)
• Drug Interactions
• Glioma (drug therapy, metabolism, pathology)
• Heterocyclic Compounds, 3-Ring (pharmacology)
• Humans
• Molecular Targeted Therapy
• Neoplasm Invasiveness
• Phosphorylation
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Receptors, Notch (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Thiadiazoles (pharmacology)