title: Neuroendocrine phenotype alteration and growth suppression through apoptosis by MK-2206, an allosteric inhibitor of AKT, in carcinoid cell lines in vitro.
abstract: 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.affiliation: Endocrine Surgery Research Laboratories, Department of Surgery and University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705, USA.
authors.forename: Yash
authors.initials: Y
authors.lastname: Somnay
authors.forename: Kevin
authors.initials: K
authors.lastname: Simon
authors.forename: April D
authors.initials: AD
authors.lastname: Harrison
authors.forename: Selvi
authors.initials: S
authors.lastname: Kunnimalaiyaan
authors.forename: Herbert
authors.initials: H
authors.lastname: Chen
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Kunnimalaiyaan
mesh_terms: D000494:Allosteric Regulation; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001984:Bronchial Neoplasms / Q000188:drug therapy / Q000473:pathology; D002276:Carcinoid Tumor / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D051057:Proto-Oncogene Proteins c-akt