RESUMO
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.
Assuntos
Dipeptidases/metabolismo , Dipeptidil Peptidases e Tripeptidil Peptidases/metabolismo , Leucemia/tratamento farmacológico , Sesquiterpenos/uso terapêutico , Linhagem Celular Tumoral , Humanos , Leucemia/enzimologia , Reação em Cadeia da Polimerase em Tempo RealRESUMO
This article describes the framework and strategies that the London Health Sciences Centre has developed to foster trusting and collaborative relationships with its regional partners in Southwestern Ontario. A four-phase approach was used to identify, implement and evaluate system-wide opportunities to improve the integration of clinical care in Southwestern Ontario. Specific case studies are illustrated that used this framework to improve both access to patient services and length of stay, while positively affecting operating resources.