Myeloperoxidase expression as a potential determinant to parthenolide-induced apoptosis in leukemia bulk and leukemia stem cells

Abstract

Since parthenolide (PTL) is an effective anti-leukemic agent, it is important to identify molecular marker to predict response to PTL. In this study, the roles of myeloperoxidase (MPO) in determining the sensitivity of leukemia cells to PTL-induced apoptosis were evaluated. PTL induced apoptosis via reactive oxygen species (ROS) generation and mitochondria-mediated caspase activation occurred to a greater extent in MPO-high leukemia cell lines (HL60, NB4, Kasumi, and wild-type MPO-overexpressing K562) compared to MPO-low cell lines (U937, K562, and mutant MPO-transfected K562). Pretreatment of MPO-high leukemia cells with MPO inhibitor, ABAH or ScAc, abrogated PTL-induced apoptosis, indicating that MPO molecule is critically involved in PTL-induced apoptosis. PTL-induced apoptosis was accompanied by downregulation of NF-B, Bcl-L, Mcl-1, XIAP, and survivin. PTL-induced apoptosis was observed selectively in primary acute myeloid leukemia (AML) cells expressing higher level of MPO ( 50%) while sparing primary AML cells with lower level of MPO and normal hematopoietic stem cells (HSC). PTL-induced apoptosis rate in CD34+CD38- cell fraction was greater in MPO-high AML as compared to MPO-low AML (P<0.01) and normal CD34+ HSC (P<0.01). Nonobese diabetic/severe combined immunodeficient xenograft leukemia model revealed that PTL preferentially target AML CD34+CD38- population. Taken together, this data suggest that MPO plays a crucial role in determining the sensitivity of leukemia cells to PTL-induced cell death and that PTL can be considered as a promising leukemia stem cells-targeted therapeutic agent for AML with high level of MPO.