Document Detail


FTY720 shows promising in vitro and in vivo preclinical activity by downmodulating Cyclin D1 and phospho-Akt in mantle cell lymphoma.
MedLine Citation:
PMID:  20460491     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Despite the progress that has been made in the treatment of mantle cell lymphoma (MCL), all patients invariably relapse with the currently available therapies. Because of the absence of curative therapy for MCL, we explored FTY720 as a novel agent against MCL. EXPERIMENTAL DESIGN: The cytotoxic effect of FTY720 in primary MCL tumor cells and cell lines were evaluated in vitro. The effects of FTY720 on caspase activation, generation of reactive oxygen species, and modulation of Cyclin D1 and Akt, which are implied in the pathogenesis of MCL, were investigated. The in vivo efficacy of FTY720 was evaluated in a Jeko-severe combined immunodeficient xenograft model of human MCL. RESULTS: FTY720 mediated time- and dose-dependent cytotoxicity in primary MCL tumor cells and MCL cell lines in vitro. FTY720-induced cytotoxicity occured independent of caspase activation but dependent on the generation of ROS in MCL. In addition, FTY720 treatment resulted in the time-dependent downmodulation of Cyclin D1 and accumulation of cells in G(0)-G(1) and G(2)-M phases of the cell cycle with concomitant decrease in S-phase entry. Furthermore, concentrations of FTY720 that induced cytotoxicity led to decreased phospho-Akt in primary MCL cells and cell lines. Most importantly, the in vivo therapeutic activity of FTY720 was shown in severe combined immunodeficient mice engrafted with the Jeko MCL cell line. CONCLUSIONS: These results provide the first evidence for a potential use of FTY720 in targeting key pathways that are operable in the pathogenesis of MCL and warrant further investigation of FTY720 in clinical trials to treat patients with MCL.
Authors:
Qing Liu; Lapo Alinari; Ching-Shih Chen; Fengting Yan; James T Dalton; Rosa Lapalombella; Xiaoli Zhang; Rajeswaran Mani; Teresa Lin; John C Byrd; Robert A Baiocchi; Natarajan Muthusamy
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-05-11
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  16     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-16     Completed Date:  2010-08-20     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3182-92     Citation Subset:  IM    
Copyright Information:
(c) 2010 AACR.
Affiliation:
Division of Pharmaceutics, College of Pharmacy, the Ohio State University, Columbus, Ohio 43210, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / therapeutic use*
Apoptosis
Cell Cycle
Cell Line, Tumor
Cyclin D1 / metabolism*
Female
Humans
Lymphoma, Mantle-Cell / drug therapy*
Mice
Mice, SCID
Propylene Glycols / therapeutic use*
Proto-Oncogene Proteins c-akt / metabolism*
Reactive Oxygen Species / metabolism
Sphingosine / analogs & derivatives*,  therapeutic use
Xenograft Model Antitumor Assays
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Propylene Glycols; 0/Reactive Oxygen Species; 123-78-4/Sphingosine; 136601-57-5/Cyclin D1; 162359-55-9/fingolimod; EC 2.7.11.1/Proto-Oncogene Proteins c-akt

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


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