CN110585443A - 一种抑制胶质瘤侵袭性生长的复合物及其应用 - Google Patents
一种抑制胶质瘤侵袭性生长的复合物及其应用 Download PDFInfo
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Abstract
本发明属于生物医药技术领域,具体涉及一种抑制胶质瘤侵袭性生长的复合物及其应用和一种体外非治疗抑制胶质瘤侵袭性生长的方法。所述复合物为格瑞克霉素B—RhoA蛋白复合物,格瑞克霉B通过与RhoA蛋白的THR37,GLN63,ASP120的残基形成氢键连接。本发明提供的复合物可有效抑制胶质瘤侵袭性生长,具有很好的抗肿瘤作用;体外非治疗抑制胶质瘤侵袭性生长的方法可有效在体外抑制胶质瘤侵袭性生长的能力;同时也可制造体外低侵袭性的胶质瘤模型,可用于实验室的课题研究。
Description
技术领域
本发明属于生物医药技术领域,具体涉及一种抑制胶质瘤侵袭性生长的复合物及其应用和一种体外非治疗抑制胶质瘤侵袭性生长的方法。
背景技术
恶性肿瘤是严重危害人类健康的高发病率和高致死率疾病。胶质瘤(glioma)是由神经外胚层分化而来的胶质细胞(星形胶质细胞、少突胶质细胞和室管膜等)引发的肿瘤,在颅内肿瘤中发病率位列第一。根据WHO2007年中枢神经系统肿瘤分类,恶性胶质瘤定义为高于或等于WHOⅢ级的胶质细胞瘤,具体包括间变性星形细胞瘤(Ⅲ级)、间变性少突胶质细胞瘤(Ⅲ级)、间变性少突星形细胞瘤(Ⅲ级)、胶质母细胞瘤(Ⅳ级)和巨细胞胶质母细胞瘤(Ⅳ级),其中前三者可统称为“间变性胶质瘤”。恶性胶质瘤是颅内最常见的恶性肿瘤,恶性胶质瘤的发病率约为5~8/10万,约占所有胶质细胞瘤的50%。在美国,每年新增病例有14000例,近20年来发病率呈上升趋势。而且,因恶性胶质瘤呈浸润性无限制增生、与正常脑组织无明显界限并富含血管,还具有高复发率和低治愈率。虽经多年努力,其死亡率和致残率仍很高,间变型星形细胞瘤的中位生存期为2~5年,胶质母细胞瘤仅为12~15个月。
目前恶性胶质瘤的治疗已发展为手术、放疗和化疗联合的综合治疗模式。各治疗方法在改善患者生存、提高患者生活质量方面协同发挥作用,由于恶性胶质瘤具有侵袭性强的特点,致使神经外科手术无法完全切除,而后续进行的放疗和化疗又难以彻底地消除残存肿瘤细胞,这些细胞最终引起肿瘤的复发,导致患者预后差,死亡率高。恶性胶质瘤对传统的放疗和化疗不敏感,即使经过多年发展,目前治疗效果仍并不能令人满意,并且手术后一旦复发,愈后差,平均生存时间只有12~15个月。
目前从海洋微生物代谢产物中,发现了几类化合物结构新颖、抗肿瘤细胞生物活性强,海洋微生物代谢产物已经成为国内外抗癌药物研究与开发的热点。格瑞克霉素系列化合物是深海放线菌次级代谢产物,最开始发现格瑞克霉素能够抑制小鼠白血病细胞P388的生长。目前已研究证实了格瑞克霉素系列化合物能够抑制肿瘤细胞的增殖并诱导其凋亡,具有抗HepG2肝癌,SW-1990胰腺癌,HeLa宫颈癌,NCI-H460肺癌和MCF-7乳腺癌的作用。但迄今为止,格瑞克霉素系列化合物是否具有抑制胶质瘤肿瘤的作用以及是如何抑制胶质瘤肿瘤生长的尚未见报道。
发明内容
本发明的目的之一在于提供一种抑制胶质瘤侵袭性生长的复合物,所述复合物可抑制胶质瘤侵袭性生长。
为实现上述目的,本发明采用以下方案:
所述复合物为格瑞克霉素B—RhoA蛋白复合物,格瑞克霉B通过与RhoA蛋白的THR37,GLN63,ASP120的残基形成氢键连接。
进一步,所述复合物通过影响RhoA蛋白的下游信号抑制胶质瘤侵袭性生长。
本发明的目的之二在于提供一种体外非治疗抑制胶质瘤侵袭性生长的方法,该方法可有效在体外抑制胶质瘤侵袭性生长的能力。同时也可制造体外低侵袭性的胶质瘤模型,可用于实验室的课题研究。
为实现上述目的,本发明采用以下方案:
所述方法为在体外培养胶质瘤细胞株,再用所述的复合物进行处理,处理后用Transwell和Western Blotting检测验证胶质瘤的生长情况。
进一步,所述胶质瘤细胞株为胶质瘤细胞株U251。
进一步,所述血清为无血清的DMEM培养基。
进一步,所述Western Blotting检测胶质瘤细胞的MMP2和N-Cadherin的蛋白表达。
进一步,复合物处理的时间为24小时。
本发明的目的之三在于提供一种所述复合物的一种应用,具体为在制备抑制胶质瘤侵袭性生长药物中的应用。
为实现上述目的,本发明采用以下方案:
所述复合物通过影响RhoA蛋白的下游信号抑制胶质瘤侵袭性生长。
进一步,所述复合物通过抑制胶质瘤细胞克隆抑制胶质瘤侵袭性生长。
本发明的有益效果在于:
1)本发明提供的复合物可有效抑制胶质瘤侵袭性生长,具有很好的抗肿瘤作用;
2)本发明提供的利用所述复合体外非治疗抑制胶质瘤侵袭性生长的方法可有效在体外抑制胶质瘤侵袭性生长的能力。同时也可制造体外低侵袭性的胶质瘤模型,可用于实验室的课题研究;
3)所述复合物在抑制胶质瘤细胞侵袭性生长的药物中具有巨大潜力。
附图说明
图1实施例1Transwell实验结晶紫染色。
图2实施例1Transwell实验细胞计数。
图3Western Blotting检测侵袭相关的MMP2和N-Cadherin蛋白表达。
图4实施例3结晶紫染色和细胞计数图。
图5基因芯片分析图。
图6分子对接图。
具体实施方式
所举实施例是为了更好地对本发明进行说明,但并不是本发明的内容仅局限于所举实施例。所以熟悉本领域的技术人员根据上述发明内容对实施方案进行非本质的改进和调整,仍属于本发明的保护范围。
实施例1 Transwell实验
A.胶质瘤细胞株U251分别用DMSO,1.0μM,2.0μM的GCN B预处理24小时;
B.融化好的Matrigel放置于冰上,Matrigel与无血清的DMEM培养基1:9(V/V)混合均匀,取10μl置于24-Well Transwell(孔径0.8μm,Millipore公司)小室上室迪度,轻轻地均匀铺,切无产生气泡,37℃放置半小时;
C.取预处理好24小时的GBM细胞3*104个重悬于200μl无血清培养基,放置于铺好Matrigel的小室里,Transwell小室放置24孔板中,里面放有500μl含10%血清的DMEM培养基;
D.孵育24小时后,取出Transwell小室用PBS轻轻清洗3次,然后4%细胞固定液固定15分钟;
E.Transwell小室用PBS轻轻清洗3次,结晶紫染色15分钟,用棉签轻轻地擦去除掉小室上层内未侵袭过去的细胞;
F.Transwell小室放置于200u倍显微镜下,随机选取8个视野对细胞计数。
如图1-2所示,2.0μM GCN B预处理的细胞株的侵袭迁移能力被明显抑制,细胞数量与对照组相比也显著降低。
实施例2 Western Blotting检测侵袭相关的MMP2和N-Cadherin蛋白表达
A.收集胶质瘤细胞株U251分别用DMSO,0.5μM,1.0μM的GCN B预处理48小时的蛋白;
B.定量分析蛋白含量;
C.相同含量的蛋白进行Western Blotting检测,一、二抗的浓度按照说明书进行更改优化;
D.显影及对其图片定量分析。
结果如图3所示,1.0μM的GCN B预处理组的MMP2和N-Cadherin蛋白表达显著降低。MMP2(基质金属蛋白酶2)是基质金属蛋白酶家族(MMPs)成员之一,MMP2蛋白即明胶酶A,是一种分子量为72kD大小的Ⅳ型胶原酶,是一种降解Ⅳ型胶原的蛋白水解酶。肿瘤细胞侵袭和转移过程的重要环节就是溶解、穿越基底膜,而基底膜的主要纤维成分就是Ⅳ型胶原。间质性表型标记物N-Cadherin可调控细胞的粘附性,影响细胞的极性、形态和运动等,N-Cadherin在恶性胶质瘤里高表达,对胶质瘤的侵袭转移发挥关键的调控作用。说明GCN B有效降低胶质瘤侵袭转移能力。
实施例3低浓度格瑞克霉素B—RhoA蛋白复合物有效抑制胶质瘤迁移
A.胶质瘤细胞株U251分别用DMSO,1.0μM,2.0μM的GCN B预处理24小时;
B.取预处理好24小时的GBM细胞3*104个重悬于200μl无血清培养基,放置于Transwell小室内,然后放置24孔板中,里面放有500μl含10%血清的DMEM培养基;
C.孵育6小时后,取出Transwell小室用PBS轻轻清洗3次,然后4%细胞固定液固定15分钟;
D.Transwell小室用PBS轻轻清洗3次,结晶紫染色15分钟,用棉签轻轻地擦去除掉小室上层内未侵袭过去的细胞;
E.Transwell小室放置于200u倍显微镜下,随机选取6个视野对细胞计数。
结果如图4所示,GCN B预处理的胶质瘤细胞迁移能力显著降低。恶性胶质瘤具有独特的高侵袭迁移能力,胶质瘤细胞往往浸润性侵袭周边正常脑组织,导致外科手术难以切干净,从而导致胶质瘤复发治疗失败。GCN B能够有效抑制迁移能力,说明GCN B是一个非常有前景治疗胶质瘤迁移能力的化合物。
实施例4基因芯片分析
胶质瘤细胞株U251分别用DMSO,1.0μM,2.0μM的GCN B预处理48小时,然后基因芯片分析,对于差异1.5倍,P值<0.05的基因进行Signal-Net分析,如图5所示RhoA为核心基因(最高分9.3631).
实施例5.Western Blotting检测RhoA蛋白表达
A.收集胶质瘤细胞株U251分别用DMSO,0.5μM,1.0μM的GCN B预处理48小时的蛋白;
B.定量分析蛋白含量;
C.相同含量的蛋白进行Western Blotting检测,一、二抗的浓度按照说明书进行更改优化;
D.显影及对其图片定量分析。
如图5所示,1.0μM的GCN B处理的细胞株RhoA蛋白表达显著降低。
实施例6分子对接格瑞克霉素与RhoA蛋白结合位点
通过SYBYL-X 2.0软件,应用Surflex-Dock GeomX对GCN B与RhoA的复合物的分子对接研究,如图6所示,发现RhoA的THR37,GLN63,ASP120的残基参与了氢键连接,在GCN B与RhoA的结合中起重要作用。
最后说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的宗旨和范围,其均应涵盖在本发明的权利要求范围当中。
Claims (10)
1.一种抑制胶质瘤侵袭性生长的复合物,其特征在于,所述复合物为格瑞克霉素B—RhoA蛋白复合物,格瑞克霉B通过与RhoA蛋白的THR37,GLN63,ASP120的残基形成氢键连接。
2.根据权利要求1所述的复合物,其特征在于,所述复合物通过影响RhoA蛋白的下游信号抑制胶质瘤侵袭性生长。
3.一种体外非治疗抑制胶质瘤侵袭性生长的方法,其特征在于,在体外培养胶质瘤细胞株,再用权利要求1所述的复合物进行处理,处理后用Transwell和Western Blotting检测验证胶质瘤的生长情况。
4.根据权利要求3所述的方法,其特征在于,所述胶质瘤细胞株为胶质瘤细胞株U251。
5.根据权利要求3所述的方法,其特征在于,所述血清为无血清的DMEM培养基。
6.根据权利要求3所述的方法,其特征在于,所述Western Blotting检测胶质瘤细胞的MMP2和N-Cadherin的蛋白表达。
7.根据权利要求3所述的方法,其特征在于,复合物处理的时间为24小时。
8.权利要求1所述的复合物在制备抑制胶质瘤侵袭性生长药物中的应用。
9.根据权利要求8所述的应用,其特征在于,所述复合物通过影响RhoA蛋白的下游信号抑制胶质瘤侵袭性生长。
10.根据权利要求8所述的应用,其特征在于,所述复合物通过抑制胶质瘤细胞克隆抑制胶质瘤侵袭性生长。
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