Abstract
Substance P (SP) regulates multiple biological processes through its high-affinity neurokinin-1 receptor (NK-1R). While the SP/NK-1R signaling axis is involved in the pathogenesis of solid cancer, the role of this signaling pathway in hematological malignancy remains unknown. Here, we demonstrate that NK-1R expression is markedly elevated in the white blood cells from acute myeloid leukemia patients and a panel of human leukemia cell lines. Blocking NK-1R induces apoptosis in vitro and in vivo via increase of mitochondrial reactive oxygen species. This oxidative stress was triggered by rapid calcium flux from the endoplasmic reticulum into mitochondria and, consequently, impairment of mitochondrial function, a mechanism underlying the cytotoxicity of NK-1R antagonists. Besides anticancer activity, blocking NK-1R produces a potent antinociceptive effect in myeloid leukemia-induced bone pain by alleviating inflammation and inducing apoptosis. These findings thus raise the exciting possibility that the NK-1R antagonists, drugs currently used in the clinic for preventing chemotherapy-induced nausea and vomiting, may provide a therapeutic option for treating human myeloid leukemia.
Highlights
Neurokinin-1 receptor is an effective target for treating leukemia by inducing oxidative stress through mitochondrial calcium overload
All myeloid leukemia cell lines presented moderate to strong expression of neurokinin-1 receptor (NK-1R) (Fig. 1C) and Substance P (SP) (Fig. 1D and SI Appendix, Fig. S1B), whereas lack of positive staining for both NK-1R and SP was observed in all 10 healthy volunteers
This study further defined mitochondrial oxidative stress as a key factor contributing to the proapoptotic effect of NK-1R antagonists
Summary
Neurokinin-1 receptor is an effective target for treating leukemia by inducing oxidative stress through mitochondrial calcium overload. Besides anticancer activity, blocking NK-1R produces a potent antinociceptive effect in myeloid leukemia-induced bone pain by alleviating inflammation and inducing apoptosis. These findings raise the exciting possibility that the NK-1R antagonists, drugs currently used in the clinic for preventing chemotherapyinduced nausea and vomiting, may provide a therapeutic option for treating human myeloid leukemia. Despite tremendous efforts in developing effective therapeutics for treating acute myeloid leukemia (AML), this hematological disease remains an incurable malignancy. We show surprising findings that neurokinin-1 receptor (NK-1R) is highly expressed in AML patients and that targeting NK-1R produced potent proapoptotic and antinociceptive effects. Our study provides another example of drug discovery by mechanistic efforts
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