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Inhibition of intracellular dipeptidyl peptidases 8 and 9 enhances parthenolide's anti-leukemic activity.
MedLine Citation:
PMID:  23318959     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Parthenolide is selectively toxic to leukemia cells; however, it also activates cell protective responses which may limit its clinical application. Therefore, we sought to identify agents that synergistically enhance parthenolide's cytotoxicity. Using a high-throughput combination drug screen, we identified the hypoglycemic, vildagliptin, which synergized with parthenolide to induce death of the leukemia stem cell line, TEX (combination index (CI) = 0.36 and 0.16, at EC 50 and 80, respectively; where CI < 1 denotes statistical synergy). The combination of parthenolide and vildagliptin reduced the viability and clonogenic growth of cells from acute myeloid leukemia patients and had limited effects on the viability of normal human peripheral blood stem cells. The basis for synergy was independent of vildagliptin's primary action as an inhibitor of dipeptidyl peptidase (DPP) IV. Rather, using chemical and genetic approaches we demonstrated that the synergy was due to inhibition of the related enzymes DPP8 and 9. In summary, these results highlight DPP8 and 9 inhibition as a novel chemosensitizing strategy in leukemia cells. Moreover, these results suggest that the combination of vildagliptin and parthenolide could be useful for the treatment of leukemia.Leukemia accepted article preview online, 15 January 2013; doi:10.1038/leu.2013.9.
Authors:
P A Spagnuolo; R Hurren; M Gronda; N Maclean; A Datti; A Basheer; F-H Lin; X Wang; J Wrana; A D Schimmer
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-15
Journal Detail:
Title:  Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K     Volume:  -     ISSN:  1476-5551     ISO Abbreviation:  Leukemia     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
School of Pharmacy, University of Waterloo, Kitchener Ontario, Canada.
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