CN108478809A - 一种天然小分子hec-23在制备用于促进溶酶体介导的细胞死亡的药物中用途 - Google Patents
一种天然小分子hec-23在制备用于促进溶酶体介导的细胞死亡的药物中用途 Download PDFInfo
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Abstract
本发明提供一种化学生物学筛选体系构建方法,包括以下步骤:使用24孔板培养秀丽隐杆线虫;设置不同实验组;将24孔板包好锡箔纸,保证避光、防止照射;放入摇床培养;48或72小时之后,将培养的线虫放入载玻片,置于显微镜下观察线虫体腔中类巨噬细胞中溶酶体膜稳态的变化。本发明还提供一种经过上述化学生物学筛选体系构建方法筛选出的促进溶酶体介导的细胞坏死的天然小分子化合物,及其在制备用于促进溶酶体介导的细胞坏死的疾病的药物中的用途。
Description
技术领域
本发明涉及化学生物学领域,尤其涉及生物医药领域,特别涉及化学生物学筛选体系,以及一种促进溶酶体介导的细胞坏死的天然小分子化合物HEC-23及其类似物的用途。
背景技术
溶酶体是细胞内一种单层膜结构的酸性细胞器(pH 4.5-5.0),是胞内物质降解和代谢调控的重要场所。溶酶体功能紊乱导致人类多种重大疾病的发生,包括溶酶体蓄积病(Lysosomal Storage Disorders,LSD)、神经退行性疾病、代谢性疾病和肿瘤等。溶酶体膜的完整性不仅影响质子泵v-ATPase等溶酶体膜蛋白的功能,而且对于维持水解酶定位和底物降解后的运输起重要作用。因此,揭示溶酶体膜稳态的调控是一个重要的科学问题。研究表明,ceramide/sphingosine等脂类代谢紊乱导致溶酶体膜通透性增加,化学物质如vacuolin-1也通过影响磷脂酰肌醇代谢引发相似结果。但细胞如何通过蛋白或信号通路主动调节溶酶体膜的稳态仍不清楚。因此,本发明人通过构建模式生物线虫的化学筛选体系来研究此技术问题。另外,肿瘤细胞中存在凋亡机制的缺失(如caspase突变失活),且临床常发生肿瘤对化疗药物的抗药性,现有技术中仍没有效果良好的办法克服这一障碍。
发明内容
本发明的目的在于:(1)构建一种化学生物学筛选体系,并通过该体系来探索溶酶体膜稳态的研究;(2)基于该体系筛选出可通过诱导溶酶体介导的细胞死亡(LysosomalCell Death,LCD)而促进人类肿瘤细胞死亡、提高化疗效果的小分子化合物HEC-23及其类似物,为临床治疗肿瘤提供候选药物。
为了实现上述目的,本发明采用的构建化学生物学筛选体系的方法是:该体系在模式生物-秀丽隐杆线虫(Caenorhabditis elegans,C.elegans)中建立。将线虫进行液体培养,每1升培养液体包含2~4g KH2PO4,4~7gNa2HPO4,4~6g NaCl和0.5~1mmol/L MgSO4。优选的,1升培养液中包含:3g KH2PO4,6g Na2HPO4,5g NaCl and 1mmol/L MgSO4,同时加入X1666大肠杆菌(E.coli.的一种)做为线虫的食物。所述X1666大肠杆菌与所述培养液体的体积比为1:45~55。优选的,X1666大肠杆菌与培养液的体积比为1:50。培养在细胞培养用的24孔板进行,即每孔挑入L4生长阶段(线虫幼虫分L1-L4四个阶段)的线虫25只,加入500微升的培养液(包含X1666大肠杆菌)。随后设置不同实验组:如空白组(不加化合物),加入对照试剂组,对照试剂可选用DMSO(二甲基亚砜),加入各种小分子化合物组。同时设置不同剂量,优选的为0,1mM,10mM,30mM,100mM,300mM等剂量(在线虫体系剂量是mM;在肿瘤细胞体系剂量是μM)。完成后,将24孔板包好锡箔纸(保证避光、防止照射)并放入摇床培养(摇床控制在100~140转/分钟,优选120转/分钟,温度控制在10~30摄氏度,优选20摄氏度)。48或72小时之后,培养结束,将培养的线虫放入载玻片,置于激光显微镜或相差显微镜下观察,检测线虫体腔中类巨噬细胞中溶酶体体积的变化,构建化学生物学筛选体系。
通过上述方法构建的化学生物学筛选体系可用于筛选天然小分子化合物,当加入了小分子化合物的实验组后续观察到溶酶体体积发生明显变化,可知该小分子化合物具有诱导溶酶体特异增大的作用,从中可以筛选出具有诱导溶酶体介导的细胞坏死(LCD)作用的小分子化合物。
本发明还提供一种通过上述方法构建的化学生物学筛选体系筛选出的天然小分子化合物,其具有诱导溶酶体特异增大的作用,进而具有诱导溶酶体介导的细胞坏死(LCD)作用。根据本发明的方法筛选出HEC-23,正式学术名称是Ervachinine B,以及具有相似结构和相似生物学功能的化合物Ervachinine A、C、D(下称HEC-23的类似物)。结构如下:
上述天然小分子化合物优选HEC-23,其在本发明构建的化学生物学筛选体系中可以促使溶酶体水解酶cathepsin进入细胞质,由此导致溶酶体介导的细胞坏死(LCD),进而可以杀死多种人类肿瘤细胞。因此本发明进而要求上述天然小分子化合物在制备治疗基于溶酶体介导的细胞坏死的疾病的药物中的应用。
优选的,本发明的上述天然小分子化合物因为具有诱导溶酶体介导的细胞坏死(LCD)作用,其与化疗药物顺铂联用具有显著的协同增强效应,联合使用可显著降低顺铂剂量。因此本发明的上述天然小分子化合物还可以和化疗药物顺铂联用,用于使诱导的LCD达到为临床治疗肿瘤、降低化疗药物剂量和提高化疗效果的用途。
由此,本发明提供了天然小分子HEC-23及其类似物在制备增大溶酶体及抑制增大溶酶体成熟的药物中的应用。
本发明提供了天然小分子HEC-23及其类似物在制备增加溶酶体膜通透性、促进溶酶体水解酶进入细胞质的药物中的应用。
本发明提供了天然小分子HEC-23及其类似物在制备促进溶酶体介导的细胞坏死的药物中的应用。
本发明提供了天然小分子HEC-23及其类似物在制备抗肿瘤药物中的应用,所述肿瘤为宫颈癌,肝癌细,乳腺癌细胞或白血病。
本发明提供了天然小分子HEC-23及其类似物在制备提高化疗药物顺铂的肿瘤杀伤效果并降低化疗药物顺铂剂量的药物中的应用。
本发明天然小分子HEC-23及其类似物用作药物时,可以直接使用,或以药学上可接受的盐以及药物组合物的形式使用。
本发明所述的天然小分子化合物HEC-23可以通过现有技术制备,例如,将构成HEC-23的两个吲哚单体分别在吲哚环或其他环上引入相应的取代基进行必要的修饰,然后在醇(例如甲醇、乙醇)溶液中经酸催化,在适当的温度下(例如常温到回流的温度,具体地20~80℃)进行偶联,从而制备而成。
发明效果
与现有技术相比,本发明的优点在于:
(1)本发明所述的以秀丽隐杆线虫构建的生物线虫的化学筛选体系可以清楚的观察、检测溶酶体膜稳态变化,并可以通过该筛选体系了解细胞如何通过蛋白或信号通路主动调节溶酶体膜的稳态。该筛选体系还具有以下优势:
a)线虫有6个类巨噬细胞,并具有活跃的内吞功能,因此该体系有利于天然小分子摄取;
b)利用荧光探针可动态观测“内吞体-溶酶体”的变化;
c)线虫类巨噬细胞中溶酶体融合/分裂变化明显,利于分析膜稳态的变化;
d)线虫有丰富的突变体,利于遗传筛选和阐明机制。
(2)本发明通过生物线虫的化学筛选体系筛选出的天然小分子化合物HEC-23具有促使溶酶体水解酶cathepsin L进入细胞质,从而导致溶酶体介导的细胞坏死的作用。该作用可以a)用以杀死多种人类肿瘤细胞,达到治疗多种癌症的效果;b)与化疗药物顺铂具有显著的协同增强效应,联合使用可显著降低顺铂剂量。
综上所述,本发明的发明效果在于可以通过构建的生物化学筛选体系观察、检测溶酶体膜稳态变化,筛选出溶酶体介导的细胞坏死的天然小分子化合物,用于临床治疗肿瘤、降低化疗药物剂量和提高化疗效果。
附图说明
图1:HEC-23特异增大LAMP-1阳性的溶酶体,不显著影响Rab5阳性的早期内吞体和Rab7阳性的晚期内吞体图;
图2:HEC-23增大后的溶酶体酸化被抑制图;
图3:HEC-23增大后的溶酶体不再成熟图;
图4:HEC-23诱导溶酶体膜通透性增大图;
图5:HEC-23诱导水解酶cathepsin L的释放图;
图6:HEC-23诱导溶酶体介导的细胞坏死图;
图7:抑制HEC-23诱导的细胞坏死图;
图8:HEC-23诱导多种人类肿瘤细胞的死亡图;
图9:MTT法检测细胞存活的情况图;
图10:HEC-23与不同剂量的Cisplatin(顺铂)单独、共同处理HeLa细胞存活图;
图11:HEC-23与不同剂量的Cisplatin单独、共同处理HepG2细胞存活图;
图12:HEC-23与不同剂量的Cisplatin单独、共同处理MCF-7细胞存活图;
图13:HEC-23与不同剂量的Cisplatin单独、共同处理HL-60细胞存活图。
具体实施方式
下面结合实施例对本发明作进一步说明,但这些实施例不构成对本发明的保护范围的限制。
本发明采用的天然小分子HEC-23的化学生物学筛选体系构建方法:
该体系在模式生物-秀丽隐杆线虫(Caenorhabditis elegans,C.elegans)中建立。将线虫进行液体培养,培养液体(1升培养液包含:3g KH2PO4,6g Na2HPO4,5g NaCl and1mmol/L MgSO4),同时加入X1666细菌做为线虫的食物,X1666细菌与培养液的体积比为1:50。培养在细胞培养用的24孔板进行,即每孔挑入L4生长阶段的线虫25只,加入500微升的培养液,包含X1666细菌。随后设置不同实验组:如不加化合物、加入对照组试剂DMSO(二甲基亚砜)、加入各种小分子化合物。同时设置不同剂量(0,1mM,10mM,30mM,100mM,300mM)等剂量。完成后,将24孔板包好锡箔纸(保证避光、防止照射)并放入摇床培养(摇床120转/分钟,温度控制在20摄氏度)。48或72小时之后,培养结束,将培养的线虫放入载玻片,置于激光显微镜或相差显微镜下观察,检测线虫体腔中类巨噬细胞中溶酶体体积的变化。
实施例1:HEC-23诱导人宫颈癌细胞系(HeLa)细胞死亡
在培养的人HeLa细胞中加入10μM的HEC-23,处理3小时后,发现HEC-23特异增大LAMP-1阳性的溶酶体,但不显著影响Rab5阳性的早期内吞体和Rab7阳性的晚期内吞体,如附图1所示。
实施例2
向HeLa细胞转染mCherry-LAMP1质粒特异标记溶酶体,用10μM的HEC-23处理3小时后,加入1μM溶酶体酸化的荧光探针LysoSensor并染色30分钟。之后发现HEC-23增大的溶酶体中LysoSensor染色明显降低,说明增大的溶酶体不能正常酸化,如附图2所示。
实施例3
BODIPY pepstatin A可以特异结合活化的溶酶体水解酶cathepsin D,可指示溶酶体的成熟。用10μM的HEC-23处理HeLa细胞3小时后,加入BODIPY pepstatin A染色30分钟,发现HEC-23增大的溶酶体中BODIPYpepstatin A染色明显降低,说明增大的溶酶体不能成熟,如附图3所示。
实施例4
蛋白Galectin3(Gal)可以特异高效地结合膜内侧糖基化蛋白的β-半乳糖甙(β-galactoside),因此可以检测溶酶体是否发生破裂。用10μM的HEC-23处理HeLa细胞3小时后,增大的溶酶体中EGFP-Gal明显富集,说明增大的溶酶体膜稳定性被破坏、通透性增大,如附图4所示。
实施例5
在HEC-23增大溶酶体膜通透性的同时,溶酶体水解酶cathepsin L不能定位于增大的溶酶体中而进入细胞质,而体积正常的溶酶体中含有水解酶cathepsin L。这说明水解酶cathepsin L从膜通透性增大的溶酶体中泄漏出来,如附图5所示。
实施例6
由于水解酶cathepsin L的泄漏,提示HEC-23可能导致细胞死亡,因此,进行了如下实验:用10μM的HEC-23处理HeLa细胞,12小时后发现细胞明显死亡。进行Annexin V和PI染色后,发现细胞呈现染色双阳性,说明HEC-23破坏细胞膜、诱导的是细胞坏死而非细胞凋亡,如附图6所示。
实施例7
溶酶体水解酶cathepsin L家族的特异抑制剂CA-074-Me和细胞坏死的抑制剂IM-54,可以显著抑制HEC-23诱导的细胞坏死,这说明HEC-23通过增加溶酶体膜通透性、促进溶酶体水解酶cathepsin L进入细胞质、导致细胞坏死,及溶酶体介导的细胞坏死(LCD),如附图7所示。图中,*指有统计学显著差异,分别表示*<0.05,**<0.01,***<0.001。
实施例8
其他人类肿瘤细胞,例如人肝癌细胞系HepG2、人乳腺癌细胞MCF-7、人早幼粒白血病细胞HL-60,按照实施例1中对HeLa采用相同的步骤和方法进行实验,其结果如附图8所示。
实施例9:
为验证HEC-23与化疗药物顺铂Cisplatin有协同增强效应,在HeLa细胞上做了如下实验。
固定100μM的Cisplatin单独处理的剂量,随后设置0-30μM不同剂量的HEC-23单独处理组和0-30μM不同剂量的HEC-23与100μM的Cisplatin的共同处理组,12小时后用MTT法检测细胞存活的情况,如附图9所示(图中,*指有统计学显著差异,分别表示*<0.05,**<0.01,***<0.001):
(a)单独处理时,HEC-23的剂量需要到达10μM或以上才显著地杀死肿瘤细胞;
(b)Cisplatin单独处理可有效地促进肿瘤细胞死亡,处理12小时后仅剩约40%细胞存活;
(c)当HEC-23与Cisplatin双重处理时,HEC-23在3μM时就显著增强Cisplatin杀伤肿瘤细胞的效率(与Cisplatin单独处理组相比);随HEC-23剂量的增加,这种增强效应愈发显著;
(d)HEC-23相同剂量下,双重处理组杀伤肿瘤细胞的效果都比HEC-23单独处理组的更加明显。
实施例10:
固定3μM的HEC-23的剂量,检测其与0-200μM不同剂量的Cisplatin处理HeLa细胞是否仍具有协同增强效应,如附图10所示(图中,*指有统计学显著差异,分别表示*<0.05,**<0.01,***<0.001),HEC-23+Cispaltin双重处理比相同剂量下Cisplatin单独处理更有效地促进肿瘤细胞的死亡;与HEC-23协同处理时,10μM低剂量Cisplatin杀死肿瘤细胞的效果和100μM高剂量Cisplatin单独处理的效果相同。
实施例11-13:
分别对HepG2、MCF-7、HL-60细胞系采用实施例5-6中对HeLa细胞的相同步骤和方法进行实验,结果HEC-23+Cisplatin与单独处理相比,杀死肿瘤细胞的作用都更加显著,如附图11-13所示(图中,*指有统计学显著差异,分别表示*<0.05,**<0.01,***<0.001)。
以上对本发明所提供的一种化学生物学筛选体系构建方法,以及由该方法筛选出的天然小分子化合物在制备用于促进溶酶体介导的细胞死亡的药物中用途进行了详尽介绍,本文中应用了具体个例对本发明的原理及实施方式进行了阐述,以上实施的说明只是用于帮助理解本发明的方法及其核心思想;同时,对于本领域的一般技术人员,依据本发明的思想,在具体实施方式及应用范围上均会有改变之处,对本发明的变更和改进将是可能的,而不会超出附加权利要求所规定的构思和范围,综上所述,本说明书内容不应理解为对本发明的限制。
Claims (17)
1.一种化学生物学筛选体系构建方法,其特征在于,包括以下步骤:
步骤一:使用细胞培养板对秀丽隐杆线虫进行液体培养;
步骤二:设置不同实验组;
步骤三:将细胞培养板包好锡箔纸,保证避光、防止照射;
步骤四:将步骤三中的细胞培养板放入摇床培养,所述摇床温度控制在10~30摄氏度,所述摇床控制在100~140转/分钟;
步骤五:48或72小时之后,将培养的线虫放入载玻片,用显微镜观察检测线虫体腔中类巨噬细胞中溶酶体膜稳态的变化,构建化学生物学筛选体系。
2.根据权利要求1所述的化学生物学筛选体系构建方法,其特征在于,所述步骤一中的每1升培养液体包含2~4g KH2PO4,4~7g Na2HPO4,4~6g NaCl和0.5~1mmol/L MgSO4。
3.根据权利要求2所述的化学生物学筛选体系构建方法,其特征在于,所述培养液体还包含X1666大肠杆菌,所述X1666大肠杆菌与所述培养液体的体积比为1:45~55。
4.根据权利要求3所述的化学生物学筛选体系构建方法,其特征在于,所述步骤一中液体培养的具体操作为:选用细胞培养用的24孔板,每孔挑入L4生长阶段的线虫25只,加入500微升的培养液对线虫进行培养。
5.根据权利要求1-4任一项所述的化学生物学筛选体系构建方法,其特征在于,步骤二的所述实验组包括空白组,分别加入不同剂量的对照试剂组及小分子化合物组。
6.根据权利要求1-5任一项所述的化学生物学筛选体系构建方法,其特征在于,构建化学生物学筛选体系,筛选出促进溶酶体介导的细胞坏死的天然小分子化合物。
7.根据权利要求6所述的化学生物学筛选体系构建方法筛选出的促进溶酶体介导的细胞坏死的天然小分子化合物的用途,其特征在于,所述天然小分子化合物诱导人类肿瘤细胞的死亡,所述人类肿瘤细胞包括人宫颈癌细胞、人肝癌细胞、人乳腺癌细胞、人早幼粒白血病细胞。
8.根据权利要求6所述的促进溶酶体介导的细胞坏死的天然小分子化合物的用途,其特征在于,所述天然小分子化合物与化疗药物顺铂混合后具有显著的协同增强效应,提高所述化疗药物顺铂的肿瘤杀伤效果。
9.根据权利要求8所述的促进溶酶体介导的细胞坏死的天然小分子化合物的用途,其特征在于,所述天然小分子化合物可以降低所述化疗药物顺铂的剂量。
10.一种药物组合物在制备预防或治疗用于促进溶酶体介导的细胞坏死的疾病的药物中的应用,其中所述疾病包括肝癌、白血病、胰腺癌、乳腺癌及肺癌,其特征在于,所述药物组合物包含根据权利要求1~6任一项所述化学生物学筛选体系构建方法筛选出的天然小分子化合物。
11.根据权利要求10所述的药物组合物,其特征在于该药物组合物包含化疗药物顺铂和所述天然小分子化合物的联用。
12.根据权利要求7-9任一项所述的用途,其特征在于,所述天然小分子化合物为HEC-23及其类似物。
13.天然小分子HEC-23及其类似物在制备增大溶酶体及抑制增大溶酶体成熟的药物中的应用。
14.天然小分子HEC-23及其类似物在制备诱导溶酶体膜通透性增大、促进溶酶体水解酶释放的药物中的应用。
15.天然小分子HEC-23及其类似物在制备促进溶酶体介导的细胞坏死的药物中的应用。
16.天然小分子HEC-23及其类似物在制备抗肿瘤药物中的应用,所述肿瘤为宫颈癌,肝癌细,乳腺癌细胞或白血病。
17.天然小分子HEC-23及其类似物在制备提高化疗药物顺铂的肿瘤杀伤效果并降低化疗药物顺铂剂量的药物中的应用。
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