Neurokinin-1 receptor is an effective target for treating leukemia by inducing oxidative stress through mitochondrial calcium overload.
Chentao GeHemiao HuangFeiyan HuangTianxin YangTengfei ZhangHongzhang WuHanwei ZhouQi ChenYue ShiYanfang SunLiangjue LiuXi WangRichard B PearsonYihai CaoJian KangCaiyun FuPublished in: Proceedings of the National Academy of Sciences of the United States of America (2019)
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.
Keyphrases
- oxidative stress
- acute myeloid leukemia
- nk cells
- bone marrow
- diabetic rats
- endoplasmic reticulum
- endothelial cells
- reactive oxygen species
- signaling pathway
- dna damage
- allogeneic hematopoietic stem cell transplantation
- induced apoptosis
- ischemia reperfusion injury
- high glucose
- dendritic cells
- poor prognosis
- primary care
- pain management
- squamous cell carcinoma
- chemotherapy induced
- newly diagnosed
- body composition
- end stage renal disease
- endoplasmic reticulum stress
- epithelial mesenchymal transition
- drug induced
- spinal cord injury
- anti inflammatory
- patient reported outcomes
- long non coding rna
- soft tissue
- postmenopausal women
- acute lymphoblastic leukemia
- spinal cord
- childhood cancer
- heat shock
- neuropathic pain