Journal article
MK-2206, a novel allosteric inhibitor of Akt, synergizes with gefitinib against malignant glioma via modulating both autophagy and apoptosis
Molecular cancer therapeutics, Vol.11(1), pp.154-164
01/2012
DOI: 10.1158/1535-7163.MCT-11-0606
PMCID: PMC3302182
PMID: 22057914
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.
Details
- Title: Subtitle
- MK-2206, a novel allosteric inhibitor of Akt, synergizes with gefitinib against malignant glioma via modulating both autophagy and apoptosis
- Creators
- Yan Cheng - Department of Pharmacology and The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine and Milton S Hershey Medical Center, Hershey 17033, USAYi Zhang - Penn State Milton S. Hershey Medical CenterLi Zhang - Soochow UniversityXingcong RenKathryn J Huber-KeenerXiaoyuan LiuLei ZhouJason LiaoHeike KeihackLi YanEric RubinJin-Ming Yang
- Resource Type
- Journal article
- Publication Details
- Molecular cancer therapeutics, Vol.11(1), pp.154-164
- Publisher
- United States
- DOI
- 10.1158/1535-7163.MCT-11-0606
- PMID
- 22057914
- PMCID
- PMC3302182
- ISSN
- 1535-7163
- eISSN
- 1538-8514
- Grant note
- R01 CA135038 / NCI NIH HHS R01CA135038 / NCI NIH HHS R01 CA135038-03 / NCI NIH HHS
- Language
- English
- Date published
- 01/2012
- Academic Unit
- Obstetrics and Gynecology
- Record Identifier
- 9983931742702771
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