Neurokinin-1 receptor is an effective target for treating leukemia by inducing oxidative stress through mitochondrial calcium overload.

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.

• Authors: Chentao Ge, Hemiao Huang, Feiyan Huang, Tianxin Yang, Tengfei Zhang, Hongzhang Wu, Hanwei Zhou, Qi Chen, Yue Shi, Yanfang Sun, Liangjue Liu, Xi Wang, Richard B Pearson, Yihai Cao, Jian Kang, Caiyun Fu
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 116 Issue 39 Pg. 19635-19645 (09 24 2019) ISSN: 1091-6490 [Electronic] United States
• PMID: 31488714 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 the Author(s). Published by PNAS.

Chemical References

• Neurokinin-1 Receptor Antagonists
• Receptors, Neurokinin-1
• Substance P
• Calcium

Topics

• Adult
• Aged
• Animals
• Apoptosis (drug effects)
• Calcium (metabolism)
• Cell Line, Tumor
• Female
• Humans
• Inflammation (metabolism)
• Leukemia (therapy)
• Leukemia, Myeloid, Acute (therapy)
• Male
• Mice
• Mice, Inbred ICR
• Middle Aged
• Mitochondria (drug effects, metabolism)
• Neurokinin-1 Receptor Antagonists (pharmacology)
• Oxidative Stress
• Receptors, Neurokinin-1 (metabolism)
• Signal Transduction (drug effects)
• Substance P (metabolism, pharmacology)