Neuroendocrine phenotype alteration and growth suppression through apoptosis by MK-2206, an allosteric inhibitor of AKT, in carcinoid cell lines in vitro. Anticancer Drugs 2013 Jan;24(1):66-72
Date
11/14/2012Pubmed ID
23147412Pubmed Central ID
PMC3510354DOI
10.1097/CAD.0b013e3283584f75Scopus ID
2-s2.0-84870934216 (requires institutional sign-in at Scopus site) 22 CitationsAbstract
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.
Author List
Somnay Y, Simon K, Harrison AD, Kunnimalaiyaan S, Chen H, Kunnimalaiyaan MMESH terms used to index this publication - Major topics in bold
Allosteric RegulationAntineoplastic Agents
Apoptosis
Bronchial Neoplasms
Carcinoid Tumor
Cell Line, Tumor
Cell Proliferation
Dose-Response Relationship, Drug
Heterocyclic Compounds, 3-Ring
Humans
Lung Neoplasms
Neuroendocrine Tumors
Pancreatic Neoplasms
Phenotype
Phosphorylation
Proto-Oncogene Proteins c-akt
