Parthenolide's anti‐leukemic stem cell activity is enhanced by the inhibition of dipeptidyl peptidase 8 and 9

Abstract

Parthenolide (PTL) is the bioactive component of the medicinal plant, Feverfew, and is sold as an herbal extract for the treatment of migraines. It induces specific toxicity to leukemia stem cells; however, PTL also activates cell protective effects that limit its clinical application. Therefore, we sought to identify agents that synergistically enhance PTL's stem cell cytotoxicity. Using a high‐throughput combination drug screen, we identified the oral hypoglycemic, vildagliptin, which synergized with PTL 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 PTL and vildagliptin reduced the viability of cells from acute myeloid leukemia patients but had no effect 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) 4. Rather, using chemical and genetic approaches we demonstrated that the synergy was due to inhibition of the related enzymes DPP 8 and 9. In summary, these results highlight DPP 8 and 9 inhibition as a novel chemosensitizing strategy in leukemia stem cells. Moreover, these results suggest that the combination of vildagliptin and PTL could be useful for the treatment of leukemia.