Neurokinin-1 receptor is an effective target for treating leukemia by inducing oxidative stress through mitochondrial calcium overload
Neurokinin-1 receptor is an effective target for treating leukemia by inducing oxidative stress through mitochondrial calcium overload
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Neurokinin-1 受体是通过线粒体钙超载诱导氧化应激来治疗白血病的有效靶点
DOI：
10.1073/pnas.1908998116
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发表时间：
2019-09-24
影响因子：
11.1
通讯作者：
Fu, Caiyun
中科院分区：
文献类型：
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作者：
Ge, Chentao;Huang, Hemiao;Fu, Caiyun
尽管在开发治疗急性髓性白血病（AML）的有效疗法方面做出了巨大努力，但这种血液疾病仍然是不可治愈的恶性肿瘤。在这里，我们显示了令人惊讶的发现，神经激肽-1受体（NK-1 R）在AML患者中高度表达，靶向NK-1 R产生了有效的促凋亡和抗伤害作用。鉴于NK-1 R拮抗剂用于治疗化疗诱导的不良反应的临床可用性，NK-1 R拮抗剂的治疗效果可以容易地在患有髓性白血病的人类患者中进行测试。如果这种治疗效果在人类患者中得到成功验证，我们的发现将为数百万患者带来希望和益处。我们的研究提供了另一个通过机械努力发现药物的例子。P物质（SP）通过其高亲和力的神经激肽-1受体（NK-1 R）调节多种生物学过程。虽然SP/NK-1 R信号传导轴参与实体癌的发病机制，但该信号传导途径在血液恶性肿瘤中的作用仍然未知。在这里，我们证明，NK-1 R的表达显着升高的白色血细胞从急性髓细胞白血病患者和一组人白血病细胞系。阻断NK-1 R通过增加线粒体活性氧诱导细胞凋亡。这种氧化应激是由从内质网到线粒体的快速钙流触发的，因此，线粒体功能受损，这是NK-1 R拮抗剂细胞毒性的潜在机制。除了抗癌活性，阻断NK-1 R通过减轻炎症和诱导细胞凋亡在髓性白血病诱导的骨痛中产生有效的抗伤害感受作用。因此，这些发现提出了一种令人兴奋的可能性，即NK-1 R拮抗剂，目前用于临床预防化疗引起的恶心和呕吐的药物，可能为治疗人类骨髓性白血病提供一种治疗选择。
Significance Despite tremendous efforts in developing effective therapeutics for treating acute myeloid leukemia (AML), this hematological disease remains an incurable malignancy. Here, 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. Given the clinical availability of the NK-1R antagonists for treating chemotherapy-induced adverse effects, the therapeutic effect of the NK-1R antagonists could be readily tested in human patients with myeloid leukemia. If the therapeutic effect is successfully validated in human patients, our findings would bring hope and benefits for millions of patients. Our study provides another example of drug discovery by mechanistic efforts. 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.