title: Inhibition of intracellular dipeptidyl peptidases 8 and 9 enhances parthenolide's anti-leukemic activity.
abstract: Parthenolide is selectively toxic to leukemia cells; however, it also activates cell protective responses that 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 anti-hyperglycemic, vildagliptin, which synergized with parthenolide to induce death of the leukemia stem cell line, TEX (combination index (CI)=0.36 and 0.16, at effective concentration (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 DPP9. In summary, these results highlight DPP8 and DPP9 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.
authors: School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada. paul.spagnuolo@uwaterloo.ca
authors: P A
authors: PA
authors: Spagnuolo
authors: R
authors: R
authors: Hurren
authors: M
authors: M
authors: Gronda
authors: N
authors: N
authors: MacLean
authors: A
authors: A
authors: Datti
authors: A
authors: A
authors: Basheer
authors: F-H
authors: FH
authors: Lin
authors: X
authors: X
authors: Wang
authors: J
authors: J
authors: Wrana
authors: A D
authors: AD
authors: Schimmer
mesh_terms: D045744:Cell Line, Tumor; D004150:Dipeptidases / Q000378:metabolism*; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology; D060888:Real-Time Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000627:therapeutic use*
chemical_list: D012717:Sesquiterpenes; C002669:parthenolide; D004150:Dipeptidases; C471241:DPP9 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C487997:DPP8 protein, human