| MK-2206, a novel allosteric inhibitor of Akt, synergizes with gefitinib against malignant glioma via modulating both autophagy and apoptosis. | |
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MedLine Citation:
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PMID: 22057914 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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 exploit 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 co-treatment 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 demonstrated 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. Based on 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. |
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Authors:
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Yan Cheng; Yi Zhang; Li Zhang; Xingcong Ren; Kathryn J Huber-Keener; Xiaoyuan Liu; Lei Zhou; Jiangang Jason Liao; Heike Keihack; Li Yan; Eric H Rubin; Jin-Ming Yang |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-11-4 |
Journal Detail:
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Title: Molecular cancer therapeutics Volume: - ISSN: 1538-8514 ISO Abbreviation: - Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-11-7 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101132535 Medline TA: Mol Cancer Ther Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1Pharmacology, Penn State College of Medicine. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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