Neurokinin-2 receptor antagonist SR48968 induced necroptosis of myeloid leukemia cells by calcium overload-driven reactive oxygen species accumulation

Increasing evidence highlight tachykinin receptors as a prominent player in hematological malignancy.We previously revealed the proto-oncogenic role of neurokinin-1 receptor(NK-1R)in acute myeloid leukemia(AML),1 whereas the role of neurokinin-2 receptor(NK-2R)has not been elucidated.Herein,we found NK-2R was significantly up-regulated in AML patients in The Cancer Genome Atlas databases.This result was further confirmed in blood from AML patients and a range of human leukemia cells.Then,we verified that blocking NK-2R by SR48968 markedly promoted cell death in human myeloid leukemia without cytotoxicity to normal cells.Mechanically,we uncovered that SR48968 induced cytotoxicity through necroptosis mediated by calcium overload-driven reactive oxygen species(ROS)accumulation.In summary,our results propose that NK-2R antagonist SR48968 may be used as a new therapeutic approach for myeloid leukemia.