MK-2206, a novel allosteric inhibitor of Akt, synergizes with gefitinib against malignant glioma via modulating both autophagy and apoptosis.

Abstract

Gefitinib, a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase, has been shown to induce autophagy as well as apoptosis in tumor cells. Yet, how to use autophagy and apoptosis to improve therapeutic efficacy of this drug against cancer remains to be explored. We reported here that MK-2206, a potent allosteric Akt inhibitor currently in phase I trials in patients with solid tumors, could reinforce the cytocidal effect of gefitinib against glioma. We found that cotreatment with gefitinib and MK-2206 increased the cytotoxicity of this growth factor receptor inhibitor in the glioma cells, and the CompuSyn synergism/antagonism analysis showed that MK-2206 acted synergistically with gefitinib. The benefit of the combinatorial treatment was also shown in an intracranial glioma mouse model. In the presence of MK-2206, there was a significant increase in apoptosis in glioma cells treated with gefitinib. MK-2206 also augmented the autophagy-inducing effect of gefitinib, as evidenced by increased levels of the autophagy marker, LC3-II. Inhibition of autophagy by silencing of the key autophagy gene, beclin 1 or 3-MA, further increased the cytotoxicity of this combinatorial treatment, suggesting that autophagy induced by these agents plays a cytoprotective role. Notably, at 48 hours following the combinatorial treatment, the level of LC3-II began to decrease but Bim was significantly elevated, suggesting a switch from autophagy to apoptosis. On the basis of the synergistic effect of MK-2206 on gefitinib observed in this study, the combination of these two drugs may be utilized as a new therapeutic regimen for malignant glioma.

• Authors: Yan Cheng, Yi Zhang, Li Zhang, Xingcong Ren, Kathryn J Huber-Keener, Xiaoyuan Liu, Lei Zhou, Jason Liao, Heike Keihack, Li Yan, Eric Rubin, Jin-Ming Yang
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 1 Pg. 154-64 (Jan 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 22057914 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Apoptosis Regulatory Proteins
• BCL2L11 protein, human
• Bcl-2-Like Protein 11
• Bcl2l11 protein, mouse
• Beclin-1
• Becn1 protein, mouse
• Heterocyclic Compounds, 3-Ring
• MK 2206
• Map1lc3b protein, mouse
• Membrane Proteins
• Microtubule-Associated Proteins
• Proto-Oncogene Proteins
• Quinazolines
• RNA, Small Interfering
• ErbB Receptors
• Proto-Oncogene Proteins c-akt
• Gefitinib

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Autophagy (drug effects)
• Bcl-2-Like Protein 11
• Beclin-1
• Brain Neoplasms (drug therapy)
• Cell Line, Tumor
• Drug Synergism
• ErbB Receptors (antagonists & inhibitors)
• Gefitinib
• Glioma (drug therapy, metabolism, pathology)
• Heterocyclic Compounds, 3-Ring (pharmacology)
• Humans
• Male
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred BALB C
• Microtubule-Associated Proteins (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Quinazolines (pharmacology)
• RNA Interference
• RNA, Small Interfering