Neuroendocrine phenotypic alteration and growth suppression through apoptosis by MK-2206, an allosteric AKT inhibitor, in carcinoids
| Autor: | Somnay, Yash, Simon, Kevin, Harrison, April D., Kunnimalaiyaan, Selvi, Chen, Herbert, Kunnimalaiyaan, Muthusamy |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Lung Neoplasms
Dose-Response Relationship Drug Bronchial Neoplasms Antineoplastic Agents Apoptosis Carcinoid Tumor Article Pancreatic Neoplasms Neuroendocrine Tumors Phenotype Allosteric Regulation Cell Line Tumor Humans Phosphorylation Heterocyclic Compounds 3-Ring Proto-Oncogene Proteins c-akt Cell Proliferation |
| Popis: | Carcinoids are neuroendocrine malignancies characterized by their overproduction of various bioactive hormones that lead to the carcinoid syndrome. We have shown previously that AKT serves as a key regulator of growth and phenotypic expression of tumor markers in carcinoids by the genetic depletion of AKT expression. However, no small-molecule inhibitor of AKT kinase activity has been developed until recently. MK-2206, a novel allosteric inhibitor of AKT, is currently undergoing clinical trials for the treatment of solid tumors. In this study, we explored the effect of MK-2206 on carcinoid cell proliferation and bioactive hormone production in vitro in two carcinoid cell lines - pancreatic carcinoid BON and bronchopulmonary H727. Treatment with MK-2206 effectively suppressed AKT phosphorylation at serine 473 and significantly reduced cell proliferation in a dose-dependent manner. Most importantly, MK-2206 treatment resulted in a significant reduction in ASCL1, CgA, and NSE expression, collectively recognized as markers of neuroendocrine tumor malignancy. Furthermore, MK-2206-treated cells showed an increase in levels of cleaved PARP and cleaved caspase-3, with a concomitant reduction in levels of Mcl-1 and XIAP, indicating that the antiproliferative effect of MK-2206 occurs through the induction of apoptosis. In conclusion, MK-2206 suppresses carcinoid tumor growth, and alters its neuroendocrine phenotype, indicating that this drug may be beneficial for patients with carcinoid syndrome. These studies merit further clinical investigation. |
| Databáze: | OpenAIRE |
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