| MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. | |
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MedLine Citation:
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PMID: 20571069 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The serine/threonine kinase Akt lies at a critical signaling node downstream of phosphatidylinositol-3-kinase and is important in promoting cell survival and inhibiting apoptosis. An Akt inhibitor may be particularly useful for cancers in which increased Akt signaling is associated with reduced sensitivity to cytotoxic agents or receptor tyrosine kinase inhibitors. We evaluated the effect of a novel allosteric Akt inhibitor, MK-2206, in combination with several anticancer agents. In vitro, MK-2206 synergistically inhibited cell proliferation of human cancer cell lines in combination with molecular targeted agents such as erlotinib (an epidermal growth factor receptor inhibitor) or lapatinib (a dual epidermal growth factor receptor/human epidermal growth factor receptor 2 inhibitor). Complementary inhibition of erlotinib-insensitive Akt phosphorylation by MK-2206 was one mechanism of synergism, and a synergistic effect was found even in erlotinib-insensitive cell lines. MK-2206 also showed synergistic responses in combination with cytotoxic agents such as topoisomerase inhibitors (doxorubicin, camptothecin), antimetabolites (gemcitabine, 5-fluorouracil), anti-microtubule agents (docetaxel), and DNA cross-linkers (carboplatin) in lung NCI-H460 or ovarian A2780 tumor cells. The synergy with docetaxel depended on the treatment sequence; a schedule of MK-2206 dosed before docetaxel was not effective. MK-2206 suppressed the Akt phosphorylation that is induced by carboplatin and gemcitabine. In vivo, MK-2206 in combination with these agents exerted significantly more potent tumor inhibitory activities than each agent in the monotherapy setting. These findings suggest that Akt inhibition may augment the efficacy of existing cancer therapeutics; thus, MK-2206 is a promising agent to treat cancer patients who receive these cytotoxic and/or molecular targeted agents. |
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Authors:
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Hiroshi Hirai; Hiroshi Sootome; Yoko Nakatsuru; Katsuyoshi Miyama; Shunsuke Taguchi; Kyoko Tsujioka; Yoko Ueno; Harold Hatch; Pradip K Majumder; Bo-Sheng Pan; Hidehito Kotani |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-06-22 |
Journal Detail:
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Title: Molecular cancer therapeutics Volume: 9 ISSN: 1538-8514 ISO Abbreviation: Mol. Cancer Ther. Publication Date: 2010 Jul |
Date Detail:
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Created Date: 2010-07-09 Completed Date: 2010-11-04 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101132535 Medline TA: Mol Cancer Ther Country: United States |
Other Details:
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Languages: eng Pagination: 1956-67 Citation Subset: IM |
Copyright Information:
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(c)2010 AACR. |
Affiliation:
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Department of Oncology, Banyu Tsukuba Research Institute, Merck Research Laboratories, Tsukuba, Ibaraki 300-2611, Japan. yrdyc661@yahoo.co.jp |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Allosteric Regulation
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drug effects Animals Antineoplastic Agents / administration & dosage, pharmacology* Antineoplastic Combined Chemotherapy Protocols / therapeutic use Apoptosis / drug effects Blotting, Western Camptothecin / administration & dosage, pharmacology Carboplatin / administration & dosage, pharmacology Carcinoma, Non-Small-Cell Lung / drug therapy, metabolism, pathology Caspases / metabolism Cell Line, Tumor Cell Proliferation / drug effects Drug Synergism Enzyme Activation / drug effects Heterocyclic Compounds, 3-Ring / administration & dosage, chemistry, pharmacology* Humans Lung Neoplasms / drug therapy, metabolism, pathology Mice Molecular Structure Neoplasms / drug therapy*, metabolism, pathology Proto-Oncogene Proteins c-akt / antagonists & inhibitors*, metabolism Quinazolines / administration & dosage, pharmacology Receptor, Epidermal Growth Factor / antagonists & inhibitors, metabolism Xenograft Model Antitumor Assays |
| Chemical | |
Reg. No./Substance:
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0/Antineoplastic Agents; 0/Heterocyclic Compounds, 3-Ring; 0/MK 2206; 0/Quinazolines; 0/erlotinib; 0/lapatinib; 41575-94-4/Carboplatin; 7689-03-4/Camptothecin; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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