CN113456629A - 土木香内酯或异土木香内酯的新用途 - Google Patents
土木香内酯或异土木香内酯的新用途 Download PDFInfo
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Abstract
本发明属于医药技术领域,特别涉及土木香内酯或异土木香内酯的新用途。具体公开了土木香内酯在制备醛酮还原酶活性抑制剂中的应用;醛酮还原酶活性抑制剂,含有土木香内酯;土木香内酯在制备AKR1C1的结合底物中的应用;土木香内酯在制备AKR1C1的热稳定性增强剂中的应用;土木香内酯在制备防治AKR1C1过表达型肿瘤疾病药中的应用;肿瘤化疗辅助药物,含有土木香内酯,优选的,所述药物为抗肿瘤治疗药物敏感性降低药物。本发明针对AKR1C1过表达的肿瘤疾病提供了治疗药物,尤其针对AKR1C1过表达相关肿瘤具有突出的治疗效果;针对AKR1C1提供了有效的活性抑制剂,并且将土木香内酯作为药物中主要针对AKR1C1活性抑制的成分;同时,还为AKR1C1的检测和增强耐热性提供了途径。
Description
技术领域
本发明属于医药技术领域,特别涉及土木香内酯或异土木香内酯的新用途。
背景技术
癌症(Cancer),亦称恶性肿瘤(Malignant neoplasm)是一种严重威胁人类健康的常见病和多发病。尤其是肺癌,它是目前世界范围内最常见的恶性肿瘤,也是导致癌症患者死亡的主要病因。现阶段,治疗肺癌的治疗方法很多,其中手术仍然是首选。但是由于绝大多数肺癌患者首次就诊时就已经诊断为晚期,术后又有较高的复发率,因此术后辅助化疗是预防其复发转移的一种有效手段。目前被广泛认可的治疗方案是以铂类为主的双药联合化疗。近年来,随着分子生物的发展,越来越多的可靶向的蛋白不断被挖掘,这使得对于进展期肺癌的治疗不仅仅局限于传统化疗药物,还可以根据已经发现的作用靶点,进行药物设计开发新的靶向药物。因此,研发作用于新靶点的抗肿瘤药物具有重大意义。
醛酮还原酶1C1(Aldehyde ketone reductase family 1member 1,AKR1C1)是醛酮还原酶家族的成员之一,是人类中主要的20-酮甾体还原酶,并且在黄体酮被还原失活成20a-DHP中发挥重要作用。研究发现,AKR1C1在多种癌细胞中的含量显著高于正常细胞,而且AKR1C1的过表达可降低化疗的敏感性,是导致化疗失败的主要原因。抗癌药物一般会产生活性氧,通过不同的信号机制导致细胞功能障碍和凋亡。AKR1C1过表达可以减少活性氧的产生、消除自由基和灭活蒽环类抗癌药物,从而减少DNA的损伤和抑制细胞凋亡。近年来,有研究已证实AKR1C1与较多肿瘤的发生、发展有关。AKR1C1与肿瘤相关性的重要意义逐渐被发现。
天然产物具有丰富而多样的化学结构类型,甚至具备新药所必需的独特化学骨架,所以天然产物是发现和筛选新药的关键资源库。土木香内酯(Alantolactone,ALA)是常见的倍半萜内酯类化合物,主要来源于云木香,旋覆花,土木香根等植物。研究发现,当蛋白质与小分子药物结合时,其在热变性下趋于更加稳定。即我们可以基于细胞热稳定性变化的方法,用以监测药物在细胞或组织中的靶点蛋白结合情况。现代药理实验证实土木香内酯具有抗真菌,抗结核杆菌,抗炎,抗微生物,驱虫等多种生物活性。但是土木香内酯作为AKR1C1抑制剂的应用尚未见报道;同时通过抑制AKR1C1活性来实现部分疾病治疗的手段还需要进一步补充完善。
发明内容
针对上述问题,本发明主要针对AKR1C1过表达型肿瘤做出研究,提供治疗方案,弥补了现有针对AKR1C1活性抑制的空白,增加AKR1C1过表达引起的一些疾病的治疗手段,也弥补了肿瘤治疗中涉及AKR1C1过表达引起症状的研究空白。
为了解决上述问题,本发明采用如下技术方案:
土木香内酯或异土木香内酯作为醛酮还原酶活性抑制剂的应用,优选的,所述醛酮还原酶为AKR1C1。
醛酮还原酶活性抑制剂,含有土木香内酯或异土木香内酯,优选的,所述醛酮还原酶为AKR1C1。
土木香内酯或异土木香内酯在制备AKR1C1的结合底物中的应用。
AKR1C1的结合底物或其他等同制剂,含有土木香内酯或异土木香内酯。
土木香内酯或异土木香内酯在AKR1C1的检测试剂中的应用。
AKR1C1的检测试剂,含有土木香内酯或异土木香内酯。
土木香内酯或异土木香内酯在制备AKR1C1的热稳定性增强剂中的应用。
AKR1C1的热稳定性增强剂,含有土木香内酯或异土木香内酯。
土木香内酯或异土木香内酯在制备防治AKR1C1过表达型疾病药中的应用,优选的所述疾病为AKR1C1过表达型肿瘤,为宫颈癌或肺癌或结肠癌。
土木香内酯或异土木香内酯在制备抗肿瘤治疗药物敏感性降低药物中的应用。
肿瘤化疗辅助药物,含有土木香内酯或异土木香内酯,优选的,所述药物为抗肿瘤治疗药物敏感性降低药物。
本发明的有益效果是:
针对AKR1C1过表达的肿瘤疾病提供了治疗药物,提高了化疗效果,尤其针对AKR1C1过表达相关肿瘤具有突出的治疗效果;针对AKR1C1提供了有效的活性抑制剂,并且将土木香内酯或异土木香内酯作为药物中主要针对AKR1C1活性抑制的成分;同时,还为AKR1C1的检测和增强耐热性提供了途径。
附图说明
图1为PISA分析ALA可能靶向AKR1C1.(a)PISA分析技术原理;(b)ALA显著增强AKR1C1蛋白的热稳定性;
图2为细胞热转变分析(CETSA)技术检测ALA与AKR1C1相互结合;
图3为CETSA技术检测ALA的浓度对其与活细胞中AKR1C1结合能力的影响;
图4为表面等离子体共振(SPR)技术检测ALA与AKR1C1的结合常数:Human Aldo-Keto ENZ-496与ALA的浓度梯度结合曲线;
图5为ALA显著抑制AKR1C1酶活性.对比溶媒对照组,*,p<0.05;**,p<0.01;
图6为ALA分别加药24小时,48小时,72小时,在HeLa,HCT116,和NCI-H460细胞模型上的细胞活力-浓度的响应曲线;
图7为异位移植模型测试ALA小鼠模型中对肿瘤生长的影响结果图。
具体实施方式
下面对本发明做进一步说明:
土木香内酯或异土木香内酯作为醛酮还原酶活性抑制剂的应用,优选的,所述醛酮还原酶为AKR1C1。其中,当土木香内酯在制备醛酮还原酶活性抑制剂中应用时,也等同在本发明范围内。
醛酮还原酶活性抑制剂,含有土木香内酯或异土木香内酯,优选的,所述醛酮还原酶为AKR1C1。其中活性抑制包括表达抑制、一种表现为防止其过表达,以及表达后的抑活。且土木香内酯相对于现有常见的抑制剂具有更好的抑制效果。
土木香内酯或异土木香内酯在制备AKR1C1的结合底物中的应用。
AKR1C1的结合底物(包含其他形式物),含有土木香内酯或异土木香内酯。
土木香内酯或异土木香内酯在AKR1C1的检测试剂中的应用。
AKR1C1的检测试剂,含有土木香内酯或异土木香内酯。
土木香内酯或异土木香内酯在制备AKR1C1的热稳定性增强剂中的应用。
AKR1C1的热稳定性增强剂,含有土木香内酯或异土木香内酯。在需要对AKR1C1进行增强或保持时,可加入该增强剂,比如在通过对AKR1C1热稳定性增强来实现检测时。
土木香内酯或异土木香内酯在制备防治AKR1C1过表达型疾病(一种为AKR1C1过表达型肿瘤)药中的应用,一些表现为宫颈癌或肺癌或结肠癌,前述癌症对土木香内酯反应更加灵敏。
土木香内酯或异土木香内酯在制备抗肿瘤治疗药物敏感性降低药物中的应用。
肿瘤化疗辅助药物,含有土木香内酯或异土木香内酯,优选的,所述药物为抗肿瘤治疗药物敏感性降低药物。
实施例1:通过PISA分析,ALA靶向AKR1C1
研究发现,当蛋白质与配体结合时,其在热变性下趋于更加稳定。ProteomeIntegral Solubility Alteration(PISA)是一种高效分析鉴定药物作用靶点的方法。主要利用测定蛋白热变性曲线的线下峰面积代替测定热熔温度Tm,从而实现药物靶点鉴定的有效性和高效性。
本发明运用PISA分析方法,在热诱导变性后,配合化学蛋白组学分析,筛选出ALA与AKR1C1相互结合,具体步骤如下:
(1)本实验以NCI-H460细胞开展,设为给药组和空白组,每组各3盘细胞(10cm的细胞培养皿)。给药组细胞加ALA(30μM)处理2小时,空白组则加等量的DMSO处理同等时间。然后两组细胞均用胰酶消化解离下来,混悬在550μL的PBS中,分成10份,每份50μL置于PCR管中。再将两组细胞各十份,分别置于PCR仪中按预设好的十个不同温度点(49-58℃,)加热处理3min。合并十份样品后,两组细胞经液氮冻-融三个循环,裂解细胞,再经100,000g超高速离心获取可溶性蛋白。
(2)获取的两组细胞可溶性蛋白分别进行蛋白浓度测定,将两组蛋白浓度归一化调整为同等浓度同等体积(0.25μg/μL),再将蛋白分别加DTT(二硫苏糖醇),IAA(碘乙酰胺)进行还原化和酰基化处理。蛋白用丙酮沉淀后,用8M Urea溶液重溶,再加入胞内蛋白酶Lys-C和胰蛋白酶消化处理,获取特异性剪切的肽段。之后将不同组别的肽段,一起用同量异序质量标记TMT试剂分别进行标记处理。合并后,除盐,再进行质谱分析。
(3)质谱分析获得的原始数据,导入MaxQuant(版本1.6.10.43)进行蛋白的鉴定和定量分析。人类全蛋白组fasta文件(29Apr.2019,版本UP000005640,18596个基因)用来作为基础数据库进行Andromeda检索匹配。具体检索设定参数如下:标记方法,TMT-10标记;固定化学后修饰,半胱氨酸末端脲甲基化;消化酶类,Trypsin/P,且最大错误剪切位点为2;蛋白鉴定的FDR,限定为0.01。其他参数则均按默认设定值进行。
实验结果:如图1所示,蛋白检索鉴定完成后,将不同组别对应的同位素峰值,分别导出,作为该组别对应蛋白的浓度。进行均值计算及统计学分析,然后ALA组蛋白的均值除以空白对照组的均值作为蛋白热稳定的差异结果(ΔSm),并将log2(ΔSm)对应-log10(p-value)绘制火山图(Volcano Plot),从中找出有显著差异的且ΔSm最大的蛋白——醛酮还原酶AKR1C1,提示ALA可能靶向AKR1C1,即视作ALA的潜在靶标蛋白。
实施例2:利用细胞热转变分析(CETSA)技术检测ALA与AKR1C1相互结合
细胞热转变分析(CETSA)技术可以直接在细胞或组织内检测药物和标靶蛋白的结合亲和力,具体步骤如下:
(1)本实验以NCI-H460细胞开展,设为给药组和空白组,每组各3盘细胞(10cm的细胞培养皿)。给药组细胞加ALA(30μM)处理2小时,空白组则加等量的DMSO处理同等时间。然后两组细胞均用胰酶消化解离下来,混悬在550μL的PBS中,分成10份,每份50μL置于PCR管中。再将两组细胞各十份,分别置于PCR仪中按预设好的十个不同温度点(49-58℃,)加热处理3min。两组各十份细胞样品分别经液氮冻-融三个循环,裂解细胞,再经100,000g超高速离心获取可溶性蛋白。
(2)样品配制:从离心机中取出PCR小管,分别吸取56μL的上清液于新的1.5EP管中,尽量小心以避免吸取沉淀部分,并加入14μL的5xSDS Loading Buffer,混匀,备用;
(3)Western Blot:将SDS-PAGE凝胶按照常规方法制备完成后,放入电泳槽中,倒入适量的1×电泳缓冲液,拔去梳子,将步骤(2)准备好的样品及蛋白Marker加入到SDS-PAGE凝胶的各泳道中,用80V恒压跑胶30分钟,再用120V恒压跑胶100分钟;电泳完毕后,在200mA恒流的条件将胶上的蛋白转至PVDF膜上,转膜2小时后,用5%的脱脂牛奶(1×TBST配制)进行室温封闭1小时,根据蛋白大小将封闭完成的膜剪成条状,在4℃条件下,一抗(Tubulin和AKR1C1)孵育过夜,次日,将孵完一抗的膜置于1×TBST中,放在摇床上,洗膜3次,每次5分钟,然后室温孵育二抗(兔二抗)1小时,二抗孵育完成后,用1×TBST洗膜3次,每次5分钟,最后将膜浸泡于配制好的发光底物中,利用化学发光仪,调好曝光时间进行显影。
实验结果:如图2所示,为ALA处理细胞裂解液的CETSA结果图,从图中可知,将细胞用反复冻融法裂解成裂解液后,最后通过Western Blot技术发现,ALA的孵育能增加AKR1C1热稳定性,明显看出加药物组AKR1C1的目的条带强于对照组,即ALA与AKR1C1发生了结合,使其在加热条件下蛋白更加稳定。
实施例3:本实施例利用细胞热转变分析(CETSA)技术检测ALA的浓度对其与活细胞中AKR1C1结合能力的影响
具体步骤如下:
(1)细胞铺板:NCI-H460细胞培养至对数生长期,加入胰蛋白酶至细胞完全消化后离心,去上清,用新鲜培养基吹打混匀细胞沉淀,制成单细胞悬液,将细胞重悬液以每孔2mL的量均匀铺于6孔板中;
(2)药物处理:次日,药物组加入浓度为10mM的ALA-DMSO-培养基溶液,使其ALA终浓度分别为32μM、16μM、8μM、4μM、2μM,对照组不加,ALA终浓度视为0μM,37℃、5%CO2条件下孵育2小时;
(3)样品加热:步骤(2)孵育完成后,从培养箱取出,吸除全部培养基,用磷酸缓冲盐溶液漂洗细胞一次,并用胰蛋白酶将细胞消化下来,离心后去上清液,用磷酸缓冲盐溶液重悬细胞沉淀以洗去多余ALA,再次离心后留取细胞沉淀,共收集6管细胞沉淀,分别是:0μM(对照组)、32μM、16μM、8μM、4μM、2μM的ALA孵育细胞2小时候的样品,每管加入200μL磷酸缓冲盐溶液,重悬细胞后,以50μL的量将细胞悬液分别分至3个PCR小管,设置PCR仪的加热温度为55℃,将PCR小管放入PCR仪,进行加热,共计3分钟;
(4)反复冻融法裂解细胞:将步骤(3)加热完成后的6管PCR小管细胞分别经液氮冻-融三个循环,裂解细胞,再经100,000g超高速离心获取可溶性蛋白。
(5)样品配制:从离心机中取出PCR小管,分别吸取40μL的上清液于新的1.5EP管中,尽量小心以避免吸取沉淀部分,并加入10μL的5x SDS Loading Buffer,混匀,备用;
(6)Western Blot:同实施列2中Western Blot部分。
实验结果:如图3所示,为不同浓度的ALA处理细胞的CETSA结果图,从图中可知,用不同浓度的ALA对活细胞进行2小时的孵育,发现药物浓度越高,其与AKR1C1的结合能力越强。
实施例4:本实施例利用表面等离子体共振(SPR)技术检测ALA与AKR1C1的结合常数
具体步骤如下:
(1)按照OpenSPRTM仪器标准操作程序安装NTA芯片,开始以最大流速(150μL/min)运行,检测缓冲液含1%DMSO+1mM NADP PBS。待达到信号基线后,调整缓冲液的流速到20μL/min。
(2)开始激活芯片,取出制备好的咪唑和NiCl2溶液,通过进样口注入,完成芯片表面功能化,准备固定His标签的配体。
(3)准备溶解好的配体蛋白200μL,通过进样口注入相互作用4min。观察基线5min,以确保稳定。通过比较注入配体前后的信号测量配体结合的量。如果需要更多的配体,可以再次注入配体。
(4)配体信号稳定之后,开始注入高浓度的分析物,以确认配体的活性,并确认表面大致的最大结合能力。
(5)将流速提高到150μL/min,注入适当的再生缓冲液,以去除分析物。
(6)分析物用缓冲液稀释,浓度详见实验结果,并以20μL/min上样,蛋白与配体结合时间均为240s;自然解离300s;
实验结果:如图4所示,NTA芯片上固定的Aldo-Keto ENZ-496蛋白可结合ALA在LSPR分析中测定的亲和常数为27.2μm。
实施例5:本实施例利用酶活性试验测试ALA对AKR1C1酶活性的影响具体步骤如下:
(1)用测试缓冲液稀释rhAKR1C1至40ng/μL备用;
(2)用底物缓冲液稀释s-tetralol至4mM备用;
(3)用底物缓冲液稀释NADP+至2mM备用;
(4)取用1:1体积的4mM s-tetralol和2mM NADP+混匀成底物混合物,备用;
(5)按下面设计,除空白对照组加50μL的测试缓冲液,其他组每个孔加50μL的40ng/μL rhAKR1C1,ALA三个浓度组别分别加入1μLALA的三种储备液,混匀室温放置5min
(6)然后在以上每个孔加入49μL底物混合物开始反应;
(7)立刻用kinetic mode开启测定每个孔的吸光度(340nm),测定5min;
计算酶的活性:
*Adjusted for Substrate Blank
**Using the extinction coefficient 6270M-1cm-1
***Using the path correction 0.32cm
实验结果:如图5所示,本发明的ALA在浓度达到3μM时即可以显著抑制AKR1C1的酶活性。
实施例6:本实施例利用MTT试验测试ALA对肺癌细胞增值的影响
具体步骤如下:
(1)制备细胞悬液:收集对数期细胞,消化,重悬常规培养液中,调整细胞密度至1×105/ml;
(2)接种细胞:每个待测孔加入细胞悬液100μl,使待测细胞数量至10000个/孔,边缘孔用无菌PBS填充;
(3)药物处理:5%CO2,37℃孵育,待细胞贴壁后即可加药,设置10个梯度,每孔100ul,设3个复孔,继续在5%CO2,37℃条件下孵育24-72小时,倒置显微镜下观察;
(4)MTT染色:每个孔加入20μl的MTT溶液(5mg/ml),继续培养4h后,弃去培养液,然后在每孔加入150μl二甲基亚砜,置摇床上低速振荡10min,使结晶物充分溶解。
(5)吸光度测定:在酶联免疫检测仪OD 590nm处测量各孔的吸光值。
实验结果:如图6和表1所示,ALA可以显著抑制三种肿瘤细胞的生长,并且存在浓度与时间的依赖关系。
表1.分别加药24小时,48小时,72小时,ALA对应在HeLa,HCT116,和NCI-H460细胞模型的IC50值(μM)
实施例7:本实施例利用异位移植模型测试ALA小鼠模型中对肿瘤生长的影响
具体步骤如下:
(1)裸鼠异位移植实体瘤造模:将培养至快要融合的对数期的细胞,胰酶消化后,用PBS制成细胞密度为1×106/ml的细胞悬液,每只裸鼠皮下注射0.2ml细胞悬液,观察3-5天,待瘤体长到约100mm3开始实验;
(2)给药干预:每两天,裸鼠尾静脉给予不同剂量的ALA(5mg/kg)或者等量的溶媒;
(3)数据监测:每次给药后,用游标卡尺测量并记录肿瘤的长度和宽度,同时监测裸鼠的体重大小;
(4)结果统计:按照V=ab2/2(其中,a为瘤体长度,b为瘤体宽度),计算瘤体的体积并制作移植瘤的生长曲线,同时绘制裸鼠体重的变化曲线,评估ALA的抗肿瘤作用以及安全性。
实验结果:如图7所示,静脉注射ALA(5mg/kg)可以显著抑制小鼠的肿瘤生长,终点时的抑制率为67%,同时在给药期间,与对照组相比,小鼠的体重几乎没有变化。该结果表明,ALA可以在体内模型中有效抑制肿瘤生长,而且不会引起体重下降等副作用。
本领域的技术人员可以明确,在不脱离本发明的总体精神以及构思的情形下,可以做出对于以上实施例的各种变型。其均落入本发明的保护范围之内。本发明的保护方案以本发明所附的权利要求书为准。
Claims (10)
1.土木香内酯或异土木香内酯作为醛酮还原酶活性抑制剂的应用,优选为,土木香内酯,优选的,所述醛酮还原酶为AKR1C1。
2.醛酮还原酶活性抑制剂,其特征在于,含有土木香内酯或异土木香内酯,优选为,土木香内酯,优选的,所述醛酮还原酶为AKR1C1。
3.土木香内酯或异土木香内酯在制备AKR1C1的结合底物中的应用,优选为,土木香内酯。
4.AKR1C1的结合底物,其特征在于,含有土木香内酯或异土木香内酯,优选为,土木香内酯。
5.土木香内酯或异土木香内酯在AKR1C1的检测试剂中的应用,优选为,土木香内酯。
6.AKR1C1的检测试剂,其特征在于,含有土木香内酯或异土木香内酯,优选为,土木香内酯。
7.土木香内酯或异土木香内酯在制备AKR1C1的热稳定性增强剂中的应用,优选为,土木香内酯。
8.AKR1C1的热稳定性增强剂,其特征在于,含有土木香内酯或异土木香内酯,优选为,土木香内酯。
9.土木香内酯或异土木香内酯在制备防治AKR1C1过表达型疾病药中的应用,优选为,土木香内酯,优选的,所述疾病为AKR1C1过表达型肿瘤,为宫颈癌或肺癌或结肠癌。
10.土木香内酯或异土木香内酯在制备抗肿瘤治疗药物敏感性降低药物中的应用,优选为,土木香内酯。
肿瘤化疗辅助药物,其特征在于,含有土木香内酯或异土木香内酯,优选为,土木香内酯,优选的,所述药物为抗肿瘤治疗药物敏感性降低药物。
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