MK-2206, a novel allosteric inhibitor of Akt, synergizes with gefitinib against malignant glioma via modulating both autophagy and apoptosis*
| Autor: | Eric H. Rubin, Li Zhang, Li Yan, Yan Cheng, Xingcong Ren, Jin Ming Yang, Jiangang (Jason) Liao, Xiao yuan Liu, Yi Zhang, Kathryn J. Huber-Keener, Heike Keihack, Lei Zhou |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Male
Cancer Research Apoptosis Biology Article chemistry.chemical_compound Mice Gefitinib Glioma Cell Line Tumor Proto-Oncogene Proteins Antineoplastic Combined Chemotherapy Protocols medicine Autophagy Animals Humans Growth factor receptor inhibitor RNA Small Interfering Cytotoxicity Protein kinase B neoplasms Mice Inbred BALB C Bcl-2-Like Protein 11 Brain Neoplasms Membrane Proteins Drug Synergism medicine.disease ErbB Receptors Oncology chemistry MK-2206 Cancer research Quinazolines Beclin-1 RNA Interference Apoptosis Regulatory Proteins Heterocyclic Compounds 3-Ring Microtubule-Associated Proteins Proto-Oncogene Proteins c-akt medicine.drug |
| Popis: | 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. Mol Cancer Ther; 11(1); 154–64. ©2011 AACR. |
| Databáze: | OpenAIRE |
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