Document Detail


FTY720 induces necrotic cell death and autophagy in ovarian cancer cells: a protective role of autophagy.
MedLine Citation:
PMID:  20935520     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
FTY720, a sphingosine analog, is a novel immunosuppressant currently undergoing multiple clinical trials for the prevention of organ transplant rejection and treatment of various autoimmune diseases. Recent studies indicate an additional cytotoxic effect of FTY720 and its preclinical efficacy in a variety of cancer models, yet the underlying mechanisms remain unclear. We demonstrate here for the first time that FTY720 exhibits a potent, dose- and time-dependent cytotoxic effect in human ovarian cancer cells, even in the cells that are resistant to cisplatin, a commonly prescribed chemotherapeutic drug for treatment of ovarian cancer. In contrast to the previously reported cytotoxicity of FTY720 in many other cancer cell types, FTY720 kills ovarian cancer cells independent of caspase 3 activity and induces cellular swelling and cytoplasmic vacuolization with evident features of necrotic cell death. Furthermore, the presence of autophagic hallmarks, including an increased number of autophagosomes and the formation and accumulation of LC3-II, are observed in FTY720-treated cells before cell death. FTY720 treatment enhances autophagic flux as reflected in the increased LC3 turnover and p62 degradation. Notably, blockade of autophagy by either specific chemical inhibitors or siRNAs targeting Beclin 1 or LC3 resulted in aggravated necrotic cell death in response to FTY720, suggesting that FTY720-induced autophagy plays a self-protective role against its own cytotoxic effect. Thus, our findings not only demonstrate a new death pathway underlying the cytotoxic effect of FTY720, but also suggest that targeting autophagy could augment the anticancer potency, providing the framework for further development of FTY720 as a new chemotherapeutic agent for ovarian cancer treatment.
Authors:
Ning Zhang; Yanfei Qi; Carol Wadham; Lijun Wang; Alessandra Warren; Wen Di; Pu Xia
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-11-16
Journal Detail:
Title:  Autophagy     Volume:  6     ISSN:  1554-8635     ISO Abbreviation:  Autophagy     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-16     Completed Date:  2011-03-02     Revised Date:  2011-06-30    
Medline Journal Info:
Nlm Unique ID:  101265188     Medline TA:  Autophagy     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1157-67     Citation Subset:  IM    
Affiliation:
Signal Transduction Program, Centenary Institute; Sydney Medical School, University of Sydney, Sydney, Australia.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / drug effects
Autophagy / drug effects*
Caspases / metabolism
Cell Line, Tumor
Cisplatin / pharmacology
Cytoprotection / drug effects*
Drug Screening Assays, Antitumor
Female
Humans
Inhibitory Concentration 50
Lysophospholipids / metabolism
Necrosis
Ovarian Neoplasms / enzymology,  pathology*,  ultrastructure
Propylene Glycols / pharmacology*
Signal Transduction / drug effects
Sphingosine / analogs & derivatives*,  metabolism,  pharmacology
Chemical
Reg. No./Substance:
0/Lysophospholipids; 0/Propylene Glycols; 123-78-4/Sphingosine; 15663-27-1/Cisplatin; 162359-55-9/fingolimod; 26993-30-6/sphingosine 1-phosphate; EC 3.4.22.-/Caspases

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


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