Document Detail


Neuroendocrine phenotype alteration and growth suppression through apoptosis by MK-2206, an allosteric inhibitor of AKT, in carcinoid cell lines in vitro.
MedLine Citation:
PMID:  23147412     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Yash Somnay; Kevin Simon; April D Harrison; Selvi Kunnimalaiyaan; Herbert Chen; Muthusamy Kunnimalaiyaan
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Anti-cancer drugs     Volume:  24     ISSN:  1473-5741     ISO Abbreviation:  Anticancer Drugs     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-11-29     Completed Date:  2013-05-09     Revised Date:  2014-11-13    
Medline Journal Info:
Nlm Unique ID:  9100823     Medline TA:  Anticancer Drugs     Country:  England    
Other Details:
Languages:  eng     Pagination:  66-72     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Allosteric Regulation
Antineoplastic Agents / administration & dosage,  pharmacology*
Apoptosis / drug effects*
Bronchial Neoplasms / drug therapy,  pathology
Carcinoid Tumor / drug therapy,  pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Heterocyclic Compounds, 3-Ring / administration & dosage,  pharmacology*
Humans
Lung Neoplasms / drug therapy,  pathology
Neuroendocrine Tumors / drug therapy,  pathology
Pancreatic Neoplasms / drug therapy,  pathology
Phenotype
Phosphorylation / drug effects
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Grant Support
ID/Acronym/Agency:
P30 CA014520/CA/NCI NIH HHS; P30 CA014520/CA/NCI NIH HHS; R01 CA121115/CA/NCI NIH HHS; R01 CA121115/CA/NCI NIH HHS; R03 CA155691/CA/NCI NIH HHS; T32 CA090217/CA/NCI NIH HHS; T35 DK062709/DK/NIDDK NIH HHS; T35 DK062709/DK/NIDDK NIH HHS; //Howard Hughes Medical Institute
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Heterocyclic Compounds, 3-Ring; 0/MK 2206; EC 2.7.11.1/Proto-Oncogene Proteins c-akt
Comments/Corrections
Erratum In:
Anticancer Drugs. 2013 Jul;24(6):658

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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