CN112546050A - 齐墩果酸的医药用途 - Google Patents
齐墩果酸的医药用途 Download PDFInfo
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- CN112546050A CN112546050A CN201910918727.0A CN201910918727A CN112546050A CN 112546050 A CN112546050 A CN 112546050A CN 201910918727 A CN201910918727 A CN 201910918727A CN 112546050 A CN112546050 A CN 112546050A
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- cancer
- tumor
- purine
- oleanolic acid
- cells
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Abstract
Description
技术领域
本发明涉及中药单体齐墩果酸(I)的医药用途,具体涉及通过抑制肿瘤代谢中嘌呤补救合成通路活性发挥抗癌作用。
背景技术
肿瘤细胞的快速增殖需要遗传物质的大量合成。而核苷酸是合成细胞遗传物质的主要原料。值得注意的是,肿瘤代谢重编程对细胞中核苷酸水平起重要的调控作用。肿瘤代谢重编程对核苷酸的影响主要表现在以下两方面:a)肿瘤细胞在糖酵解途径中所产生的中间产物,为核苷酸的合成提供了原料,促进核苷酸的合成[1];b)谷氨酰胺的代谢可以加强核苷酸的合成,其代谢产物能够为核苷酸合成提供前体物质[2]。
嘌呤核苷酸是肿瘤细胞增殖的基础和必需物质[3,4],研究发现次黄嘌呤(hypoxanthine)的代谢产物肌苷(inosine)与腺苷(adenosine)的比例在肿瘤细胞中明显改变,这种变化可以影响肿瘤细胞的增殖、转移以及侵袭力[5]。
目前对靶向抑制嘌呤补救合成通路代谢酶异常活跃的治疗上市药物还未出现。在前列腺癌细胞中研究发现,中药单体黄连素能够通过增强尿酸表达而抑制前列腺癌细胞的增殖 [6]。dCTP焦磷酸酶(DCTPP1)可以通过对异常核苷酸(如5-甲基-dCTP)的高效水解,减少异常核苷酸在DNA合成中的错误,从而可能成为保证肿瘤细胞快速增殖时核酸代谢的稳定性和准确性途径之一。雷公藤甲素是一种传统的抗肿瘤中药有效成分,最新的研究显示它可以通过直接与人dCTP焦磷酸酶(DCTPP1)结合降低其酶活性发挥其抗肿瘤的作用[7]。这些都证明通过影响肿瘤代谢来抑制肿瘤的发生和发展,不仅极具实际应用价值,且由于其作用机制有别现有的治疗策略,也具备极高的科研价值。然而现阶段关于报道中药单体I抑制肿瘤代谢嘌呤补救合成通路代谢较少,因此发现及开中药单体I靶向抑制嘌呤补救合成通路代谢对肿瘤的治疗依旧十分迫切,中药单体I靶向运用于抑制嘌呤补救合成通路代谢酶发挥抗癌作用的开发具有商业及应用价值。
参考文献
[1]A.Saha,S.Connelly,J.Jiang,S.Zhuang,D.Amador,T.Phan,R.Pilz,G.J.M.C.Boss,Akt Phosphorylation and Regulation of Transketolase Is a NodalPoint for Amino Acid Control of Purine Synthesis,55(2014)264-276.
[2]C.T.Hensley,A.T.Wasti,R.J.DeBerardinis,Glutamine and cancer:cellbiology,physiology,and clinical opportunities,J Clin Invest,123(2013) 3678-3684.
[3]F.Di Virgilio,Purines,purinergic receptors,and cancer,Cancer Res,72(2012)5441-5447.
[4]A.Bahreyni,S.S.Samani,F.Rahmani,R.Behnam-Rassouli,M.Khazaei,M.Ryzhikov,M.R.Parizadeh,A.Avan,S.M.Hassanian,Role of adenosine signaling inthe pathogenesis of breast cancer,J Cell Physiol,233(2018)1836-1843.
[5]D.Dominissini,S.Moshitch-Moshkovitz,N.Amariglio,G.Rechavi,Adenosine-to-inosine RNA editing meets cancer,Carcinogenesis,32(2011) 1569-1577.
[6]X.Li,A.Zhang,H.Sun,Z.Liu,T.Zhang,S.Qiu,L.Liu,X.Wang,Metaboliccharacterization and pathway analysis of berberine protects against prostatecancer,Oncotarget,8(2017)65022-65041.
[7]T.W.Corson,H.Cavga,N.Aberle,C.M.Crews,Triptolide directly inhibitsdCTP pyrophosphatase,Chembiochem,12(2011)1767-1773.
发明内容
本发明旨在提出齐墩果酸(以下也称中药单体I或I)的医药新用途,揭示中药单体I 通过抑制肿瘤代谢中嘌呤补救合成通路代谢中代谢酶异常活跃发挥抗癌作用。
本发明提供具有式I所示的化合物齐墩果酸,或其药学上可接受的盐:
本发明还旨在揭示中药单体I或其药学上可接受的盐在通过抑制肿瘤代谢中嘌呤补救合成通路代谢酶基因异常活跃发挥抗肿瘤作用。其中所述的肿瘤为肺癌、乳腺癌、食道癌、肠癌、肾癌、唇癌、肝癌、胃癌、鼻咽癌、卵巢癌、子宫癌、胆囊癌、喉癌、脑瘤、鳞癌、血管瘤、前列腺癌、肾癌、骨癌、舌癌、淋巴癌、胰腺癌、膀胱癌、黑素瘤、白血病、皮肤癌、脂肪瘤、宫颈癌、甲状腺癌、胸腺癌。
本发明中,先通过对TCGA和GTEx数据库分析,发现嘌呤补救合成通路代谢酶异常活跃,再利用体外嘌呤补救合成通路代谢和药物的相互作用模式,结合文献和高通量筛选技术,对可能影响肿瘤代谢的中药单体进行筛选。基于上述模式,我们初步筛选了40个命中中药单体,进行了体外多种癌细胞系和正常细胞嘌呤补救合成代谢酶蛋白表达检测筛选、细胞体内嘌呤补救合成代谢酶异常高活跃抑制实验,最终获得具有抑制肿瘤代谢嘌呤补救合成通路代谢酶表达的中药单体I。
本发明中,生物活性测试结果表明,中药单体I能够抑制嘌呤补救合成通路代谢酶作用,同时中药单体I对肿瘤细胞株的生长具有一定的抑制作用。因此中药单体I可以用于靶向嘌呤补救合成代谢酶异常活跃的抗肿瘤药物的开发。
在本发明中,术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等;有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐:伯胺类、仲胺类及叔胺类,被取代的胺类,包括天然的被取代胺类、环状胺类及碱性离子交换树脂,例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
在本发明中,“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。
本发明所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本发明中,“药学上可接受的赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本发明所用的术语“治疗”和其它类似的同义词包括以下含义:
(i)预防疾病或病症在哺乳动物中出现,特别是当这类哺乳动物易患有该疾病或病症,但尚未被诊断为已患有该疾病或病症时;
(ii)抑制疾病或病症,即遏制其发展;
(iii)缓解疾病或病症,即,使该疾病或病症的状态消退;或者
(iv)减轻该疾病或病症所造成的症状。
本发明所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解,或生物系统的任何其它所需变化。例如,用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本发明公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本发明所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本发明所述化合物和方法的施用技术,在优选的实施方案中,本发明讨论的化合物和组合物通过口服施用。
本发明所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗,其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本发明所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本发明所述的化合物和至少一种协同制剂。
附图说明
图1A显示从TCGA和GTEX数据库对所有癌症正常组织和肿瘤组织之间嘌呤补救途径代谢基因转录的总分析(ACC,肾上腺皮质癌;BLCA,膀胱尿路上皮癌;BRCA,乳腺浸润癌;CESC,宫颈鳞状细胞癌和宫颈内腺癌;CHOL,胆管癌;CID,结肠腺癌;DLBC,淋巴样肿瘤弥漫性大B细胞淋巴瘤,B细胞淋巴瘤;ESCA,食管癌;GBM,多形胶质母细胞瘤;HNSC,头颈部鳞状细胞癌;KICH,肾嫌色细胞癌;KIRC,肾透明细胞癌;KIRP,肾乳头状细胞癌;LAML,急性髓性白血病;LGG,脑低级别胶质瘤;LIHC,肝细胞癌;LUad,肺腺癌;lusc,肺鳞状细胞癌;OV,卵巢浆液性囊腺癌;PAAD,胰腺腺癌;PCPG,嗜铬细胞瘤和副神经节瘤;PRAD,前列腺腺癌;READ,直肠腺癌;SARC,肉瘤;SKCM,皮肤黑色素瘤;STAD,胃腺瘤局部癌;TGCT,睾丸生殖细胞肿瘤;THCA,甲状腺癌; UCEC,子宫体子宫内膜癌;UCS,子宫癌肉瘤)。
图1B显示肺腺癌患者中,正常肺组织和肿瘤肺组织嘌呤补救合成代谢通路中不同表达的代谢物表达(n=21)。
图1C显示通过TCGA和GTEX数据库评估代谢基因转录在所有癌症中患者死亡风险之间的相关性(风险比大于1意味着死亡风险增加,而风险比小于1意味着与基因转录的较低值相比死亡风险降低)。
图1D显示Kaplan-Meier曲线显示肺腺癌患者HPRT1和NT5E表达与总生存率的关系。
图2A显示体外A549细胞增殖实验(I抑制A549细胞增殖,且呈时间依赖效应,在 48小时出现抑制,72小时显著抑制)。
图2B显示体外I处理A549细胞8h进行代谢组学检测(I处理后的嘌呤补救合成代谢物出现一致性下调)。
图2C显示Western blotting检测I处理A549细胞0h,3h,6h,8h的代谢酶HGPRT、5’-NT 蛋白水平。
图2D显示外源加入嘌呤补救合成代谢物回补A549细胞增殖实验,A549细胞恢复生长。
图2E显示用Western blotting检测增殖分子指标Proliferating Cell NuclearAntigen (PCNA)的表达发现,PCNA上调。
图3A显示Q-pcr技术检测体外I处理A549细胞嘌呤补救合成通路代谢酶HPRT1和NT5E的mRNA表达水平,发现I没有影响代谢酶的基因转录水平。
图3B显示Western blotting检测Cycloheximide(CHX)阻断I处理A549细胞嘌呤补救合成通路代谢酶HPRT1和NT5E蛋白水平,以及其蛋白降解曲线值图。
图4A显示Chloroquine(CQ)阻断了HPRT1和5’-NT酶的降解,说明I通过激活溶媒体蛋白降解途径,以及其蛋白定量图。
图4B显示Bafilomycin(BAF)阻断了I了HPRT1和5’-NT酶的降解,再一次证明I通过激活溶媒体蛋白降解途径,以及其蛋白定量图。
图4C显示中药单体I通过激活溶酶体抑制了嘌呤补救合成通路代谢酶的工作机制模式图。
图5A显示中药单体I有效地抑制了肺癌增殖。
图5B显示中药单体I有效地抑制了乳腺癌增殖。
图5C显示中药单体I有效地抑制了结肠癌增殖。
图5D显示Western blotting检测癌细胞中的嘌呤补救合成代谢酶HGPRT、5’-NT相比正常上皮细胞的蛋白表达情况,发现癌细胞中的嘌呤补救合成代谢比正常上皮细胞酶活跃。
具体实施方式
下面结合附图和具体实施例,进一步阐述本发明。这些实施例应理解为仅用于说明本发明而不用于限制本发明的保护范围。在阅读了本发明记载的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等效变化和修改同样落入本发明权利要求所限定的范围。
一、体外肿瘤细胞增殖实验--采用CCK8评价I对人源性肿瘤细胞的增殖活性。
(1)实验材料:人源性肺癌细胞A549,人源性乳腺癌细胞MDA-MB-231,人源性结肠癌细胞SW480。10%牛血清培养基,PBS溶液,胰蛋白酶(sigma),×10CCK8(sigma),中药单体I(sigma,分析纯≥97%)。
(2)实验方法:
(i)A549细胞的复苏和传代:将装有A549的细胞冻存液从-80摄氏度冰箱中取出并离心(1200rmp,3分钟),去除上层清液,加入2ml 10%牛血清培养基重悬并转入10cm培养皿,37摄氏度培养箱中孵育24小时。选取生长较好的细胞,吸取培养液,PBS清洗并用胰酶消化,离心(1200rmp,3分钟),去除上层清液,加入2ml 10%牛血清培养基重悬;
(ii)接种细胞:对上述细胞进行计数,按每孔3000-5000个细胞平均分配入各96孔板中,37摄氏度培养箱中孵育过夜;
(iii)加入0μM,20μM,80μM,100μM,200μM不同浓度的中药单体I,共孵育72小时;
(iv)吸取上层清液,每孔加入100μl 10%的CCK8培养液,孵育1-3小时(根据不同肿瘤细胞差异);
(v)酶标仪在450nm下检测各孔吸光度的变化,吸光度大小即代表活细胞数量的多少。
本实验【体外肿瘤细胞增殖实验】之实验结果如图2A,2D,5A,5B,5C所示。
二、克隆形成实验
(1)实验材料:实验材料:人源性肺癌细胞A549,10%牛血清培养基,PBS溶液,胰蛋白酶(sigma),结晶紫(sigma),中药单体I(sigma,分析纯≥97%)。
(2)实验步骤:
(i)消化A549细胞,计数后,取适量细胞加入无菌PBS洗涤。
(ⅱ)1500rpm离心5分钟,吸弃上清。
(ⅲ)加入DMEM培养基重悬细胞,保证细胞密度为200/ml,
(ⅳ)各取1ml细胞悬液加入6孔板中,保证A549均为200/孔,
(ⅴ)各孔加入不同浓度的中药单体I分别为0μM、50μM、100μM及200μM,
(ⅵ)将细胞置于细胞培养箱中培养2周左右,等待克隆长至合适大小后取出6孔板。
(ⅶ)吸弃培养液,PBS洗涤一遍。
(ⅷ)加入0.5%的结晶紫染液染色30分钟。
(ⅸ)回收结晶紫,PBS洗涤几遍后晾干,使用曝光仪拍摄肾癌细胞克隆形成情况。
本实验【克隆形成实验】之实验结果如图2A所示。
三、Western blotting技术
(1)实验材料:人源性肺癌细胞A549,人源性肺上皮细胞Beas-2B,人源性乳腺癌细胞MDA-MB-231,人源性乳腺细胞MCF-10A,人源性结肠癌细胞SW480,人源性结肠上皮细胞NCM460,10%牛血清培养基,PBS溶液,6孔板(croning),胰蛋白酶(sigma),中药单体I(sigma,分析纯≥97%),一抗(anti-cullin1 rabbit,abcom公司,2000:1稀释),二抗(IgGrabbit),蛋白裂解液,×4SDS-loading。
(2)实验方法:
(i)A549细胞,Beas-2B细胞,MDA-MB-231细胞,MCF-10A细胞,,SW480细胞,NCM460细胞的复苏和传代:将装有A549细胞,Beas-2B细胞,MDA-MB-231细胞,MCF-10A细胞, SW480细胞,NCM460细胞,冻存液从-80摄氏度冰箱中取出并离心(1200rmp,3分钟),去除上层清液,加入2ml 10%牛血清培养基重悬并转入10cm培养皿,37摄氏度培养箱中孵育24小时。选取生长较好的细胞,吸取培养液,PBS清洗并用胰酶消化,离心(1200rmp, 3分钟),去除上层清液,加入2ml 10%牛血清培养基重悬;
(ii)接种细胞:对上述细胞进行计数,按每皿50个细胞平均分配入各培养皿中,37摄氏度培养箱中孵育过夜,第二天加入中药单体I(浓度100μM-200μM)处理不同时间点;
(ⅲ)胰酶消化收集细胞,蛋白定量;
(iv)10%的SDS-PAGE制胶并进行电泳实验;
(v)转膜1小时后,20%牛奶封闭1小时,加入一抗孵育过夜;
(vi)洗膜,并加入二抗孵育1小时。
(ⅶ)显色和拍照。
本实验【Western blotting技术】之实验结果如图2A,2C,2E,3B,4A,4B,5D所示。
四、Q-pcr技术
(1)实验材料:人源性肺癌细胞A549,代谢酶HPRT1、NT5E的PCR引物,中药单体 I(sigma,分析纯≥97%),TRZol 1mL,氯仿1mL,PrimeScript RT reagent Kit(Takara),384孔PCR板
(2)实验方法:
(i)提取A549细胞RNA
1.提前一天在10cm皿种板,保证A549细胞(5×106-1×107),第二天加入中药单体I(浓度100μM-200μM)处理A549细胞0、3、6、8h后PBS洗一遍。
2.加入1mlTrizol提取细胞RNA,吹打混匀,静置10分钟。
3.每1mlTrizol加入200μl氯仿,剧烈震荡15秒,室温放置2分钟。
4.在4℃12000rpm下离心10分钟。
5.吸取上清转移至新的无RNA酶EP管中。
6.加入等体积的DEPC水配制的70%乙醇,颠倒混匀。
7.使用RNA提取试剂盒提取RNA,将所得溶液加入吸附柱中。
8.12000rpm离心1分钟,倒掉废液。
9.加入700μl的洗涤液RW1洗涤一遍,500μl的RW2洗涤2遍,离心倒掉废液。
10.将吸附柱置于室温晾干后加入50μl无RNA酶水,静置1分钟。
11.12000rpm离心收集液体即为提取的RNA,置于冰上,测量浓度后-80℃保存。
(ii)反转录
根据反转录试剂盒对上述提出的RNA进行反转录,按照如下体系。
表1.去除残余DNA
配方 | 含量 |
RNA | 1μg |
5×gDNA Eraser Buffer | 2μl |
gDNA Eraser | 1μl |
RNase Free ddH2O | 补齐至10μl |
配好上述10μl体系于PCR管中,离心至管底,置于PCR仪上,42℃反应2分钟。
表2.反转录成cDNA
配方 | 含量 |
步骤1反应液 | 10μl |
Primer script RT Enzyme Mix | 1μl |
RT primer Mix | 1μl |
5×primer script buffer | 4μl |
RNase Free ddH2O | 4μl |
配好上述20μl体系于PCR管中,离心至管底,置于PCR仪上,37℃反应15分钟,85℃反应5秒后取出。
从PCR管中取出10μl体系置于384孔PCR板,上机。
表3.qPCR反应体系
表4.qPCR循环设定体系
等待结束,分析数据。
本实验【Q-pcr技术】之实验结果如图3A所示。
综上所述:
如图1所示,实验结果表明,嘌呤补救合成通路在癌症中广泛激活。
如图2所示,实验结果表明,中药单体I抑制A549细胞中嘌呤补救合成活性抗肿瘤生长。
如图3所示,实验结果表明,中药单体I通过降解代谢酶抑制肿瘤嘌呤补救合成活性。
如图4所示,实验结果表明,中药单体I通过激活溶酶体介导蛋白降解途径下调嘌呤补救合成代谢酶。
如图5所示,实验结果表明,中药单体I可靶向于嘌呤补救合成代谢酶活跃的肿瘤治疗。
Claims (7)
2.权利要求1所述的用途,其特征是,抑制嘌呤补救合成通路相关的疾病、嘌呤补救合成通路代谢酶异常活跃的疾病是肿瘤。
3.权利要求2所述的用途,其特征是,齐墩果酸通过影响肿瘤代谢,抑制嘌呤补救合成通路活性发挥抗肿瘤作用。
4.权利要求3所述的用途,其特征是,齐墩果酸通过明显抑制各类肿瘤细胞株的嘌呤补救合成代谢酶,进而抑制肿瘤细胞增殖能力,加速肿瘤细胞死亡。
5.权利要求1-4所述的用途,其特征是,齐墩果酸的有效作用浓度为20-200μM。
6.权利要求2或3或4所述的用途,其特征是,所述的肿瘤为肺癌、乳腺癌、食道癌、肠癌、肾癌、唇癌、肝癌、胃癌、鼻咽癌、卵巢癌、子宫癌、胆囊癌、喉癌、脑瘤、鳞癌、血管瘤、前列腺癌、肾癌、骨癌、舌癌、淋巴癌、胰腺癌、膀胱癌、黑素瘤、白血病、皮肤癌、脂肪瘤、宫颈癌、甲状腺癌或胸腺癌。
7.权利要求6所述的用途,其特征是,齐墩果酸的有效作用浓度为20-200μM。
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Citations (1)
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US20090258096A1 (en) * | 2008-04-11 | 2009-10-15 | Bionovo, Inc. | Anticancer Methods Employing Extracts of Gleditsia sinensis Lam |
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US20090258096A1 (en) * | 2008-04-11 | 2009-10-15 | Bionovo, Inc. | Anticancer Methods Employing Extracts of Gleditsia sinensis Lam |
Non-Patent Citations (3)
Title |
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卫小红等: "齐墩果酸对人肺腺癌细胞A549增殖与细胞周期的阻滞作用", 《第四军医大学学报》 * |
吴林蔚等: "齐墩果酸对卵巢癌细胞IGROV1和乳腺癌细胞MDA-MB-231生长的抑制作用", 《应用与环境生物学报》 * |
塞萨尔丁.阿拉萨尔瓦等: "《干果的植物化学成分及其保健作用》", 28 February 2018, 中国质检出版社 * |
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