| PKC-alpha inhibitor MT477 slows tumor growth with minimal toxicity in in vivo model of non-Ras-mutated cancer via induction of apoptosis. | |
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MedLine Citation:
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PMID: 19795097 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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MT477 is a novel thiopyrano[2,3-c]quinoline with anti-cancer activity. The purpose of the present study was to evaluate different doses and treatment schedules of MT477 in an in vivo xenograft model of non-Ras-mutated cancer, as well as determine its biological effects and mechanism of action via the four conventional PKC isoforms: α, βI, βII, and γ. Here, we show that MT477 inhibits the activity of PKC-α and its downstream targets, ERK1/2 and Akt, before it has an effect on Ras activity. MT477 treatment of cultured H226 cells induced apoptosis and increased focal cell adhesion and formation of actin stress fibers. H226 tumor size in mice continuously treated with intraperitoneal MT477 (1 mg/kg) was 62.1 ± 15.3% smaller than the average tumor size in control mice. Blood serum chemistry revealed minimal toxicity in mice. Taken together, these results support the conclusion that MT477 acts as a direct PKC-α inhibitor in non-Ras mutated cancer, with maximum effectiveness when given in a continuous treatment schedule. |
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Authors:
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Piotr Jasinski; Pawel Zwolak; Kaoru Terai; Daniel Borja-Cacho; Arkadiusz Z Dudek |
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Publication Detail:
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Type: Journal Article Date: 2009-10-01 |
Journal Detail:
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Title: Investigational new drugs Volume: 29 ISSN: 1573-0646 ISO Abbreviation: Invest New Drugs Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-01-04 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8309330 Medline TA: Invest New Drugs Country: United States |
Other Details:
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Languages: eng Pagination: 33-40 Citation Subset: IM |
Affiliation:
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Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Mayo Mail Code 480, 420 Delaware Street SE, Minneapolis, MN, 55455, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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