Nicotinamide phosphoribosyl transferase(NAMPT)is considered as a promising target for cancer therapy to its crucial role in cancer metabolism.Despite the therapeutic potential of NAMPT enzymatic inhibitors,their effec...Nicotinamide phosphoribosyl transferase(NAMPT)is considered as a promising target for cancer therapy to its crucial role in cancer metabolism.Despite the therapeutic potential of NAMPT enzymatic inhibitors,their effectiveness is limited by dose-related toxicity and the inability to suppress nonenzymatic functions of extracellular NAMPT(e NAMPT).Herein,we designed and synthesized the first hydrophobic tagging NAMPT degraders.Among them,compound NH-11 selectively degraded NAMPT in leukemia cells through the ubiquitin-proteasome system.Compound NH-11 effectively induced apoptosis and showed low toxicity to normal cells,representing a promising anti-leukemia lead compound.?2024 Published by Elsevier B.V.on behalf of Chinese Chemical Society and Institute of Materia Medica,Chinese Academy of Medical Sciences.展开更多
目的探讨内脂素-烟酰胺磷酸核糖转移酶(Nampt)轴在卵巢上皮癌进展中的作用及对患者预后的影响。方法采用免疫组化方法检测Nampt在卵巢上皮癌及正常卵巢组织内的表达,ELISA方法测定血清内脂素浓度,并分析其与临床病理特征及患者总体生存...目的探讨内脂素-烟酰胺磷酸核糖转移酶(Nampt)轴在卵巢上皮癌进展中的作用及对患者预后的影响。方法采用免疫组化方法检测Nampt在卵巢上皮癌及正常卵巢组织内的表达,ELISA方法测定血清内脂素浓度,并分析其与临床病理特征及患者总体生存期的关系。结果卵巢上皮癌患者血清内脂素浓度显著高于卵巢良性肿瘤患者及正常对照人群,内脂素诊断卵巢上皮癌的曲线下面积(area under curve,AUC)为0.744,界值5.95 ng/mL。卵巢上皮癌患者血清内脂素与T、N、FIGO分期相关(P<0.05)且与CA125呈正相关性(rs=0.389,P=0.001)。Nampt在卵巢上皮癌组织中阳性表达率显著升高,且与FIGO分期、血清内脂素水平相关(P<0.05)。卵巢上皮肿瘤细胞Nampt蛋白表达与患者血清内脂素水平呈正相关性(rs=0.55,P<0.001)。卵巢上皮癌患者1年、3年、5年生存率分别为98.6%、74.3%、34.3%。生存分析显示,卵巢上皮癌患者生存期与T、N、FIGO分期及血清内脂素、肿瘤细胞Nampt表达有关,且FIGO分期、肿瘤细胞Nampt表达是影响患者预后的独立因素(P<0.05)。结论卵巢上皮癌患者血清内脂素、癌组织中Nampt高表达以及T、N、FIGO分期与患者总体生存期有关,且Nampt高表达、FIGO分期是独立影响因素。这提示内脂素-Nampt轴促进卵巢上皮癌进展并影响患者预后。展开更多
基金supported by the National Key Research and Development Program of China(No.2022YFC3401500 to C.S.)the National Natural Science Foundation of China(No.82030105 to C.S.)and Shanghai Rising-Star Program(No.20QA1411700 to G.D.)。
文摘Nicotinamide phosphoribosyl transferase(NAMPT)is considered as a promising target for cancer therapy to its crucial role in cancer metabolism.Despite the therapeutic potential of NAMPT enzymatic inhibitors,their effectiveness is limited by dose-related toxicity and the inability to suppress nonenzymatic functions of extracellular NAMPT(e NAMPT).Herein,we designed and synthesized the first hydrophobic tagging NAMPT degraders.Among them,compound NH-11 selectively degraded NAMPT in leukemia cells through the ubiquitin-proteasome system.Compound NH-11 effectively induced apoptosis and showed low toxicity to normal cells,representing a promising anti-leukemia lead compound.?2024 Published by Elsevier B.V.on behalf of Chinese Chemical Society and Institute of Materia Medica,Chinese Academy of Medical Sciences.
文摘目的探讨内脂素-烟酰胺磷酸核糖转移酶(Nampt)轴在卵巢上皮癌进展中的作用及对患者预后的影响。方法采用免疫组化方法检测Nampt在卵巢上皮癌及正常卵巢组织内的表达,ELISA方法测定血清内脂素浓度,并分析其与临床病理特征及患者总体生存期的关系。结果卵巢上皮癌患者血清内脂素浓度显著高于卵巢良性肿瘤患者及正常对照人群,内脂素诊断卵巢上皮癌的曲线下面积(area under curve,AUC)为0.744,界值5.95 ng/mL。卵巢上皮癌患者血清内脂素与T、N、FIGO分期相关(P<0.05)且与CA125呈正相关性(rs=0.389,P=0.001)。Nampt在卵巢上皮癌组织中阳性表达率显著升高,且与FIGO分期、血清内脂素水平相关(P<0.05)。卵巢上皮肿瘤细胞Nampt蛋白表达与患者血清内脂素水平呈正相关性(rs=0.55,P<0.001)。卵巢上皮癌患者1年、3年、5年生存率分别为98.6%、74.3%、34.3%。生存分析显示,卵巢上皮癌患者生存期与T、N、FIGO分期及血清内脂素、肿瘤细胞Nampt表达有关,且FIGO分期、肿瘤细胞Nampt表达是影响患者预后的独立因素(P<0.05)。结论卵巢上皮癌患者血清内脂素、癌组织中Nampt高表达以及T、N、FIGO分期与患者总体生存期有关,且Nampt高表达、FIGO分期是独立影响因素。这提示内脂素-Nampt轴促进卵巢上皮癌进展并影响患者预后。
