CN114712512B - 一种用于治疗her2阳性癌症的新型联合疗法 - Google Patents
一种用于治疗her2阳性癌症的新型联合疗法 Download PDFInfo
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Abstract
本发明提供了一种用于治疗HER2阳性癌症的新型联合疗法。具体地,本发明涉及将SHCBP1抑制剂和HER2抑制剂联合用于治疗HER2阳性癌症。
Description
发明领域
本发明提供了一种用于治疗HER2阳性癌症的新型联合疗法。 具体地,本发明涉及将SHCBP1抑制剂和HER2抑制剂联合用于治疗HER2阳性癌症。
发明背景
HER受体酪氨酸激酶家族的成员是细胞生长,分化和存活的重 要介导物。该受体家族包括四种独特的成员,包括表皮生长因子受体 (EGFR,ErbB1,或HER1),HER2(ErbB2或p185neu),HER3(ErbB3) 和HER4(ErbB4或tyro2)。该受体家族的成员已牵连于多种类型的人恶性肿瘤。在约16%的胃癌患者中观察到HER2的过表达。HER2 阳性的胃癌患者比HER2阴性的患者更难治疗。此外,在约20%的 人乳腺癌中也观察到HER2的蛋白质过表达或基因扩增,并且与更 具侵袭性的肿瘤、更短的复发时间和较差的总体存活相关。
赫赛汀早在1998年就被美国FDA批准用于治疗HER2阳性乳 腺癌,并且是目前唯一被批准的用于治疗HER2阳性胃癌患者的靶 向药。赫赛汀与化疗药物澳沙利铂和氟尿嘧啶联合,已成为标准的胃 癌一线化疗药物。然而,与其它癌症相比,赫赛汀治疗胃癌的效果并不令人满意。赫赛汀治疗胃癌的总有效率为47%。与单独使用化疗 药物患者相比,赫赛汀联合化疗药物将患者的总生存期提高了2.7个 月。而同样的治疗方式用于治疗乳腺癌,患者总生存期提高了4.8个 月。造成赫赛汀治疗胃癌效果不理想的主要原因在于胃癌对赫赛汀的敏感性不足,以及先天性或获得性耐药的产生。因此探究胃癌对赫赛 汀敏感性低的分子机制,并开发赫赛汀的增敏药物,对于胃癌的靶向 治疗具有重要意义。
发明内容
Shc(Src homolog and collagen homolog)是一种细胞信号转导 接头蛋白,能够被胰岛素受体(IR)、胰岛素生长因子(IGFR)、 表皮生长因子(EGFR)以及成纤维细胞生长因子等激活,在信号通 路的转导激活过程中发挥了重要作用。SHCBP1作为Shc家族的重 要成员,可与SHC蛋白SH2结构域结合,从而在细胞信号转导、细 胞分裂和癌症发生过程中也发挥着重要作用。研究显示,SHCBP1 在正常组织和生长抑制的细胞中表达较低,如脾脏、肺、心脏、肝脏等组织。而在增殖较快的细胞中表达较高,如癌细胞等。以癌症为例, SHCBP1在胃癌、淋巴瘤、乳腺癌、肺癌、神经胶质瘤、滑膜肉瘤 以及肝癌的发生发展过程中均发挥了重要作用。SHCBP1在胃癌组 织中高表达且与胃癌增殖转移相关。SHCBP1通过与PLK1直接相互作用而显著促进PLK1磷酸化MISP,从而参与胃癌细胞的有丝分 裂。
本发明人已令人惊讶地发现,SHCBP1抑制剂和HER2抑制剂 的联合使用可以有效治疗HER2阳性癌症。更具体地,本发明人发 现,SHCBP1抑制剂可以显著增强HER2抑制剂的治疗效果。更具体地,本发明人发现,茶黄素-3,3′-双没食子酸可以显著增强赫赛汀 的治疗效果。
因此,本发明提供了一种用于治疗HER2阳性癌症的新型联合 疗法。具体地,本发明涉及将SHCBP1抑制剂和HER2抑制剂联合用于治疗HER2阳性癌症。更具体地,本发明涉及将SHCBP1抑制 剂和赫赛汀联合用于治疗HER2阳性癌症。更具体地,本发明涉及 将茶黄素-3,3′-双没食子酸和赫赛汀联合用于治疗HER2阳性癌症。
如本文所用,术语“癌症”是指哺乳动物中典型特征为细胞生长 /增殖不受调控的生理疾病。癌症的例子包括但不限于鳞状细胞癌、 小细胞肺癌、非小细胞肺癌、肺腺癌、肺鳞癌、腹膜癌、肝细胞癌、 胃癌、胰腺癌、胶质瘤、宫颈癌、卵巢癌、肝癌、膀胱癌、乳腺癌、 结肠癌、结直肠癌、子宫内膜癌或子宫癌、唾液腺癌、肾癌、前列腺 癌、外阴癌、甲状腺癌、白血病和其它淋巴增殖性病症及各种类型的头颈癌。
如本文所用,术语“HER2阳性癌症”是指这样的癌症,其包含 在细胞表面上存在HER2蛋白的细胞。在本文中,HER2阳性癌症包括但不限于HER2阳性乳腺癌和胃癌。关于HER2阳性癌症的描 述可参见例如Hudziak等人,Proc.Natl.Acad.Sci.USA 84: 7159-7163(1987);Slamon等人,Science 244:707-712(1989);Slamon 等人,Science 235:177-182(1987)。
如本文所用,术语“HER2抑制剂”是抑制HER2途径信号传 导的抑制剂。在一个实施方案中,所述HER2抑制剂包括抗-HER2 抗体。抗-HER2抗体的一个例子是曲妥珠单抗(赫赛汀)。赫赛汀 可商购自例如上海罗氏制药。抗-HER2抗体的另一个例子是帕妥珠 单抗。在另一个实施方案中,所述HER2抑制剂包括HER2的小分 子抑制剂,例如抑制HER2信号传导的酪氨酸激酶抑制剂(TKI)。 HER2信号传导的小分子抑制剂的非限制性例子包括:拉帕替尼(Tykerb,GlaxoSmithKline)、CI-1033(PD183805:Pfizer)、PKI-166 (Novartis)和培利替尼EKB-569。
如本文所用,术语“SHCBP1抑制剂”是指能够实现对SHCBP1 基因及其蛋白质的抑制效果的任何物质。这可以包括例如抑制 SHCBP1基因表达的物质,例如RNA干扰(RNAi)试剂,其包括 但不限于小干扰RNA、miRNA、shRNA等。在具体的实施方案中, SHCBP1抑制剂可以选自shRNA。在具体的实施方案中,SHCBP1 抑制剂可以是SEQ ID NO:1或2所示的shRNA。
SHCBP1抑制剂还可以包括例如影响SHCBP1发挥其功能的任 何物质,例如影响SHCBP1与PLK1的相互作用从而使得SHCBP1 无法发挥参与胃癌细胞的有丝分裂的功能的物质。在具体的实施方案 中,这样的SHCBP1抑制剂可以包括但不限于茶黄素-3,3′-双没食子酸(theaflavin-3,3′-digallate)及其衍生物。本发明人已发现,茶黄 素-3,3′-双没食子酸能够抑制SHCBP1与PLK1的复合体的形成。在 其他实施方案中,这样的SHCBP1抑制剂可以包括例如茶黄素-3-没 食子酸(Theaflavin-3′-gallate)及其衍生物。在优选的实施方案中, SHCBP1抑制剂是茶黄素-3,3′-双没食子酸及其衍生物。
如本文所用,茶黄素-3,3′-双没食子酸(theaflavin-3,3′-digallate, C43H32O20)是一种红茶多酚,其分子式为:
在本文中,茶黄素-3,3′-双没食子酸可简 写为TFBG。茶黄素-3,3′-双没食子酸是可商购获得的,例如,可获 自上海陶素生化。
如本文所述,术语“衍生物”意指通过物理或化学过程从指定化合 物衍生的相似化合物,例如酯衍生物或其盐。衍生物可以使用标准程 序来制备,所述标准程序是合成有机化学领域的技术人员已知的并且 例如由J.March,“Advanced Organic Chemistry:Reactions, Mechanisms and Structure”,第4版(New York:Wiley-Interscience, 1992)描述。本领域技术人员知晓,能够获得相应化合物的衍生物而 基本上不改变其功能。
本发明人已令人惊讶地发现,茶黄素-3,3′-双没食子酸可以显著 抑制SHCBP1与PLK1的复合体的形成,并且在与HER2抑制剂(例 如赫赛汀)联合使用时,能够显著增强HER2抑制剂的功效。不受理论的限制,据信这是由于HER2激活可诱导其下游的接头蛋白 Shc1与其结合蛋白SHCBP1发生解离,释放后的Shc1与HER2结 合进而转导经典的MAPK和PI3K信号通路,而SHCBP1则被磷酸 化之后发生核转位,进入细胞核,与有丝分裂激酶PLK1形成复合体,催化有丝分裂因子MISP磷酸化,进而调控细胞有丝分裂。这也得到了临床大样本的验证(例如参见本文的图1和图2),其表明 SHCBP1在胃癌组织中显著高表达,SHCBP1的表达与HER2扩增 呈正相关,SHCBP1高表达病人其预后差。发明人还发现,另一种 茶黄素衍生物,茶黄素-3-没食子酸,也可以在一定程度上增强HER2 抑制剂的功效,但效果不如茶黄素-3,3′-双没食子酸。
因此,在一个方面,本发明涉及用于将SHCBP1抑制剂和HER2 抑制剂联合用于治疗HER2阳性癌症的方法。
在另一个方面,本发明涉及SHCBP1抑制剂和HER2抑制剂联 合用于制备用于治疗HER2阳性癌症的组合物的用途。
在另一个方面,本发明涉及一种用于治疗HER2阳性癌症的组 合物,其包含SHCBP1抑制剂和HER2抑制剂。
在另一个方面,本发明涉及一种用于治疗HER2阳性癌症的试 剂盒,其包含SHCBP1抑制剂和HER2抑制剂。
在具体的实施方案中,SHCBP1抑制剂选自RNA干扰试剂、茶 黄素-3-没食子酸和茶黄素-3,3′-双没食子酸及其衍生物。在具体的实 施方案中,SHCBP1抑制剂选自shRNA,例如SEQ ID NO:1和2 所示的shRNA。在优选的实施方案中,SHCBP1抑制剂是茶黄素-3,3′- 双没食子酸及其衍生物。
在具体的实施方案中,HER2抑制剂是赫赛汀。
在具体的实施方案中,HER2阳性癌症选自胃癌和乳腺癌。
在优选的实施方案中,本发明涉及用于将茶黄素-3,3′-双没食子 酸或其衍生物和赫赛汀联合用于治疗HER2阳性胃癌的方法。
在优选的实施方案中,本发明涉及茶黄素-3,3′-双没食子酸或其 衍生物和赫赛汀联合用于制备用于治疗HER2阳性胃癌的组合物的 用途。
在优选的实施方案中,本发明涉及一种用于治疗HER2阳性胃 癌的组合物,其包含茶黄素-3,3′-双没食子酸或其衍生物和赫赛汀。
在优选的实施方案中,本发明涉及一种用于治疗HER2阳性胃 癌的试剂盒,其包含茶黄素-3,3′-双没食子酸或其衍生物和赫赛汀。
在优选的实施方案中,本发明涉及用于将茶黄素-3,3′-双没食子 酸或其衍生物和赫赛汀联合用于治疗HER2阳性乳腺癌的方法。
在优选的实施方案中,本发明涉及茶黄素-3,3′-双没食子酸或其 衍生物和赫赛汀联合用于制备用于治疗HER2阳性乳腺癌的组合物 的用途。
在优选的实施方案中,本发明涉及一种用于治疗HER2阳性乳 腺癌的组合物,其包含茶黄素-3,3′-双没食子酸或其衍生物和赫赛汀。
在优选的实施方案中,本发明涉及一种用于治疗HER2阳性乳 腺癌的试剂盒,其包含茶黄素-3,3′-双没食子酸或其衍生物和赫赛汀。
附图说明
图1:SHCBP1在胃癌组织中表达。(A)SHCBP1在癌组织和 癌旁组织中的免疫组织化学染色结果;(B)SHCBP1免疫组织化学 染色病理评分结果;(C)SHCBP1在胃癌组织中western wlot检测 结果。
图2:胃癌组织SHCBP1表达与HER2表达相关性检测结果。 (A)SHCBP1与HER2在癌组织中相关性散点图;(B)SHCBP1 与HER2免疫组织化学染色和免疫荧光染色结果。
图3:SHCBP1可调解胃癌对赫赛汀的敏感性。(A)SHCBP1 敲除后的细胞增殖;(B)SHCBP1敲除后赫赛汀的IC50检测结果; (C)SHCBP1过表达后赫赛汀的IC50检测结果;(D)SHCBP1 敲除后赫赛汀对胃癌细胞形成克隆能力的影响;(E)SHCBP1过表 达后赫赛汀对胃癌细胞形成克隆能力的影响;(F)SHCBP1敲除后 赫赛汀对胃癌肿瘤生长的影响。
图4:FRET技术检测浓度茶黄素-3,3′-双没食子酸抑制 SHCBP1-PLK1复合体形成。(A)不同浓度茶黄素-3,3′-双没食子酸 处理细胞后FRET结果;(B)茶黄素-3,3′-双没食子酸处理细胞不同 时间后FRET结果。(平均值±SEM。*p<0.05,**p<0.01;***p< 0.001 vsCtrl/0min)
图5:茶黄素-3,3′-双没食子酸对赫赛汀的增敏结果。(A)细胞 增殖实验检测其对SNU-216细胞增敏的结果;(B)细胞增殖实验检 测其对NCI-N87细胞增敏的结果;(C-D)细胞克隆实验检测其对 SNU-216和NCI-N87细胞增敏的结果。
图6:茶黄素-3,3′-双没食子酸对赫赛汀的增敏结果。(A)腹腔 注射茶黄素-3,3′-双没食子酸对赫赛汀增敏结果;(B)小鼠肿瘤体积 结果;(C)小鼠肿瘤质量结果;(D)皮下注射注射茶黄素-3,3′-双 没食子酸对赫赛汀增敏结果;(E)小鼠肿瘤体积结果;(F)小鼠 肿瘤质量结果。
图7:茶黄素-3,3′-双没食子酸与其它茶黄素类似物增敏赫赛汀的 比较结果。
图8:赫塞汀和茶黄素-3,3′-双没食子酸联合对乳腺癌细胞 SKBR3增殖的抑制作用。平均值±SEM,*P<0.01。
序列信息
SEQ ID NO:1: CCGGCCAATTACAGTGAGTCTGATTCTCGAGAATCAGACTCACTGTAATTGGTTTTTG
SEQ ID NO:2: CCGGCTTGGTGAAACCTACAATCTTCTCGAGAAGATTGTAGGTTTCACCAAGTTTTTG
实施例:
下面将结合实施例对本发明的实施方案进行详细描述,但是本领 域技术人员将会理解,下列实施例仅用于举例说明本发明,而不应视 为限定本发明的范围。实施例中未注明具体条件者,按照常规条件或 制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可 以通过商购获得的常规产品。除非另外指明,否则本发明的实施将采用在本领域技术人员范围内的分子生物学(包括重组技术)、微生物 学、细胞生物学、生物化学和免疫学等的常规技术。这样的技术在诸 如以下的文献中充分解释:Molecular Cloning:ALaboratory Manual,second edition(Sambrook等人,1989)Cold Spring Harbor Press;Oligonucleotide Synthesis(M.J.Gait编辑,1984);Methods in Molecular Biology,Humana Press;Cell Biology:A Laboratory Notebook(J.E.Cellis编辑,1998)AcademicPress;Animal Cell Culture(R.I.Freshney编辑,1987);Introduction to Cell andTissue Culture(J.P.Mather and P.E.Roberts,1998)Plenum Press;Cell and TissueCulture:Laboratory Procedures(A.Doyle,J.B.Griffiths, and D.G.Newell编辑,1993-1998)J.Wiley and Sons;Methods in Enzymology(Academic Press,Inc.);Handbook ofExperimental Immunology(D.M.Weir and C.C.Blackwell编辑);Gene Transfer Vectorsfor Mammalian Cells(J.M.Miller and M.P.Calos编辑, 1987);Current Protocols inMolecular Biology(F.M.Ausubel等人编辑,1987);PCR:The Polymerase ChainReaction,(Mullis等人编辑, 1994);Current Protocols in Immunology(J.E.Coligan等人编辑, 1991);Sambrook and Russell,Molecular Cloning:A Laboratory Manual,3rd.ed.,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,NY(2001);Ausubel等人,Current Protocols in Molecular Biology,John Wiley&Sons,NY(2002);Harlow and Lane Using Antibodies:A Laboratory Manual,Cold Spring HarborLaboratory Press,Cold Spring Harbor,NY(1998);Coligan等人, Short Protocols inProtein Science,John Wiley&Sons,NY(2003); Short Protocols in MolecularBiology(Wiley and Sons,1999);Immunobiology(C.A.Janeway and P.Travers,1997);Antibodies(P. Finch,1997);Antibodies:a practical approach(D.Catty.编辑,IRLPress,1988-1989);Monoclonal antibodies:a practical approach(P. Shepherd andC.Dean编辑,Oxford University Press,2000);Using antibodies:a laboratory manual(E.Harlow and D.Lane(Cold Spring Harbor Laboratory Press,1999);The Antibodies(M.Zanetti and J.D.Capra编辑,Harwood Academic Publishers,1995)。
1.研究材料
茶黄素-3,3′-双没食子酸(纯度:99.49%,上海陶素生化),赫 赛汀(医用曲妥珠单抗,上海罗氏制药),胎牛血清和RPMI-1640 培养基(Gibco),MTT细胞增殖检测试剂盒(Promega),SHCBP1 抗体(sigma),HER2抗体(Abeam),PLK1抗原(Abeam), 免疫组织化学染色试剂盒(武汉博士德生物),Alexa Fluor 488荧 光二抗和Alexa Fluor 647荧光二抗(Abcam),Biacor CM5芯片(GE Healthcare),Flag抗体凝胶珠(Sigma),结晶紫染液(Solarbie), Matrige基质胶(Corning),D-虫荧光素钾(PerkinElmer)。 茶黄素(Theaflavin,TF,纯度:98.00%,上海陶素生化),茶黄素 -3-没食子酸酯(Theaflavin-3-gallate,TF2A,纯度:98.00%,上海 陶素生化),茶黄素-3′-没食子酸酯(Theaflavin-3’-gallate,TF2B,纯 度:98.00%,上海陶素生化),茶黄素-3,3′-没食子酸酯 (Theaflavin-3,3′-digallate,TFDG,纯度:98.00%,成都普瑞法科技 开发有限公司),新茶黄素(Neotheaflavin,NEO纯度:98.00%,成 都普瑞法科技开发有限公司),异茶黄素(Isotheaflavin,ISO纯度: 98.00%,成都普瑞法科技开发有限公司)
2.细胞系
胃癌细胞系NCI-N87购自中国医学科学院,胃癌细胞系SNU-216购自韩国细胞库,乳腺癌细胞SKBR3购自中国典型培养物 保藏中心细胞库。
3.实验动物
balb/c裸鼠购自北京维通利华实验动物技术有限公司。
4.人胃癌临床组织样本
所有人胃癌临床组织样本由兰州大学第二医院提供,所有患者签 署知情同意书,实验过程经过兰州大学第二医院人体伦理委员会批 准。
实施例1:SHCBP1在胃癌中的高表达
收集临床223例胃癌组织样本及其正常胃粘膜样本,4%多聚甲 醛固定并梯度脱水,石蜡包埋切片后制备为组织芯片(TMA)。组 织芯片经脱蜡至水,进行免疫组织化学染色。SHCBP1抗体以1∶200 稀释,荧光二抗以1∶200稀释。染色结束后免疫组织化学染色结果采 用KF-PRO-120扫描设备(江丰电子,宁波)成像,免疫荧光染色 采用双光子激光共聚焦显微镜成像(Zeiss,德国)成像(图1A和 1B)。利用8例胃癌患者的癌组织和癌旁组织进行Western Blot检 测(图1C)。结果表明,SHCBP1在胃癌组织中显著高表达。
利用223例胃癌病人的癌组织免疫组织化学染色和免疫荧光染 色结果表明,SHCBP1的表达与HER2表达呈正相关性,即SHCBP1 高表达的胃癌病理大多HER2也高表达(图2A和2B)。
实施例2:靶向SHCBP1的shRNA增强赫赛汀的治疗效果
构建靶向SHCBP1的shRNA(shRNA1:CCGGCCAATTACAGTGAGTCTGATTCTCGAGAATCAGACTCACTGTAATTGGTTTTTG;shRNA2: CCGGCTTGGTGAAACCTACAATCTTCTC GAGAAGATTGTAGGTTTCACCAAGTTTTTG)序列和SHCBP1的 cDNA序列,连接于稳定表达质粒并进行病毒包装,病毒转染细胞后经过嘌呤霉素筛选和单克隆筛选,得到SHCBP1敲低细胞系和SHCBP1过表达细胞系。利用MTT细胞增殖检测试剂盒检测细胞增 殖,证明构建的shRNA的功效(图3A)。
将转染或未转染上述shRNA的HER2阳性胃癌细胞SNU-216 和NCI-N87细胞培养于含10%胎牛血清的RPMI-1640培养基中, 进行传代培养后,将细胞以1×104个/mL接种于96孔板,24h后以 0ng/mL、5ng/mL、10ng/mL、50ng/mL、100ng/mL、500ng/mL、 1000ng/mL、5000ng/mL、10000ng/mL、50000ng/mL的赫赛汀处理 胃癌细胞,药物作用6天后,利用MTT细胞增殖检测试剂盒检测细 胞增殖,使用GraphPad Prism计算IC50值。
此体外实验表明,敲低SHCBP1可降低赫赛汀抑制胃癌细胞增 殖的IC50(图3B和图3D),反之,过表达SHCBP1可显著升高赫 赛汀抑制胃癌细胞增殖的IC50(图3C和图3E),说明靶向SHCBP1 的shRNA在体外可增强赫赛汀的治疗效果。
将NCI-N87细胞转染荧光素酶基因并形成稳定表达细胞株后, 以每只小鼠1×106个细胞皮下注射于balb/c裸鼠,待肿瘤生长至 100mm3时开始药物处理,药物处理结束后,麻醉小鼠并注射D-虫荧 光素钾,利用小动物成像系统(VIEWORK,Korean)对肿瘤大小进 行检测。
此体内实验表明,使用赫赛汀处理正常胃癌肿瘤,其抑制胃癌肿 瘤生长的能力较弱,然而赫赛汀处理SHCBP1敲低的胃癌组织,其 可显著抑制胃癌的生长(图3F),说明靶向SHCBP1的shRNA在 体内可增强赫赛汀的治疗效果。
实施例3:茶黄素-3,3′-双没食子酸抑制SHCBP1-PLK1复合体 的形成
我们前期利用蛋白质对接技术和点突变验证技术,确定了 SHCBP1与PLK1形成复合体的模型,并利用药物虚拟对接筛选从 17,676种化合物中筛选得到40种潜在抑制剂,并利用等离子共振技 术筛选,最终得到了靶向SHCBP1-PLK1复合体的潜在抑制剂茶黄 素-3,3′-双没食子酸。
利用荧光共振能量转移技术(FRET)检测茶黄素-3,3′-双没食子 酸抑制SHCBP1-PLK1复合体形成的能力。
首先将构建好的eYFP-SHCBP1和eCFP-PLK1质粒转染至胃癌 细胞,待细胞密度为70%左右时,加入不同浓度(0uM,10uM,20uM, 30uM,50uM)的茶黄素-3,3′-双没食子酸,30min之后,在Zeiss LSM 880激光显微镜下检测SHCBP1-PLK1复合体发生FRET的效率的 变化。将上述筛选的得到的最佳药物浓度处理细胞0h,0.Sh,1.0h, 2.0h以及3.0h后,检测FRET的效率的变化,从而判断茶黄素-3,3′- 双没食子酸对SHCBP1-PLK1复合体的影响。
结果显示,不同浓度的茶黄素-3,3′-双没食子酸处理细胞不同时 间后,可显著抑制eCFP-SHCBP1和eYFP-PLK1发生FRET的效率, 即抑制SHCBP1-PLK1形成复合体(图4A和4B)。
实施例4:茶黄素-3,3′-双没食子酸在体外增强赫赛汀的治疗效果
以HER2阳性的胃癌细胞NCI-N87与SNU-216为研究对象,将 细胞以1×104个/mL接种于96孔板中,待细胞密度为70%左右时, 用不同浓度的茶黄素-3,3′-双没食子酸(TFBG:0uM,10uM,20uM) 和赫赛汀(trast.:0.001ug/mL,0.01ug/mL,0.05ug/mL,0.1ug/mL,0.5ug/mL,1.0ug/mL,5.0ug/mL,10.0ug/mL,50.0ug/mL,100.0ug/mL) 联合使用,连续处理6天后,利用MTT细胞增殖检测试剂盒检测细胞增殖,GraphPad Prism计算IC50值(图5A和5B)。
将胃癌细胞以每培养皿1000个细胞接种于3.5cm的小培养皿 中,待细胞密度为70%左右时,对细胞分别进行不同的处理:Ctrl 组:未处理;TFBG组:10uM茶黄素-3,3′-双没食子酸处理;Trast. 组:10μg/mL赫赛汀处理;Trast.+TFBG组:10uM茶黄素-3,3′-双没食子酸联合10ng/mL赫赛汀处理。药物连续处理6天后将细胞固定 并用结晶紫染色,最后拍照进行统计分析(图5C和5D)。
结果显示,茶黄素-3,3′-双没食子酸在体外可显著增强赫赛汀对 胃癌细胞的抑制效果。
实施例4:茶黄素-3,3′-双没食子酸在体内增强赫赛汀的治疗效果
以NCI-N87细胞进行裸鼠皮下成瘤,待肿瘤体积生长至100mm3大小时,对小鼠进行随机分组,每组8只。Ctrl组:小鼠腹腔注射 安慰剂;Trast.组:小鼠腹腔注射赫赛汀10mg/kg,每周注射两次, 共三周;TFBG组:小鼠腹腔注射茶黄素-3,3′-双没食子酸50mg/kg, 每天一次,共三周;Trast.+TFBG组:小鼠腹腔注射赫赛汀10mg/kg, 每周注射两次,联合腹腔注射茶黄素-3,3′-双没食子酸50mg/kg,每 天一次,药物处理共三周。在此期间,每周测量肿瘤大小3次,待药 物处理21天时,小鼠麻醉并注射D-虫荧光素钾,利用小动物成像系 统(VIEWORK,Korean)对肿瘤大小进行检测。
以NCI-N87细胞进行裸鼠皮下成瘤,待肿瘤体积生长至100mm3大小时,对小鼠进行随机分组,每组8只。Ctrl组:小鼠腹腔注射 安慰剂;Trast.组:小鼠腹腔注射赫赛汀10mg/kg,每周注射两次, 共三周;TFBG组:小鼠皮下注射茶黄素-3,3′-双没食子酸2.5mg/kg, 每天一次,共三周;Trast.+TFBG组:小鼠腹腔注射赫赛汀10mg/kg, 每周注射两次,联合皮下注射茶黄素-3,3′-双没食子酸2.5mg/kg,每 天一次,药物处理共三周。在此期间,每周测量肿瘤大小3次,待药 物处理21天时,小鼠麻醉并注射D-虫荧光素钾,利用小动物成像系 统(VIEWORK,Korean)对肿瘤大小进行检测。
结果表明,与赫赛汀联合用药,腹腔注射或皮下注射的茶黄素 -3,3′-双没食子酸均可显著抑制胃癌的生长(图6A-F)。
实施例5:茶黄素-3,3′-双没食子酸与其它茶黄素类似物的比较 将茶黄素-3,3′-双没食子酸(TFBG)与其它药物(茶黄素(Theaflavin,TF),茶黄素-3-没食子酸酯(Theaflavin-3-gallate, TF2A),茶黄素-3′-没食子酸酯(Theaflavin-3’-gallate,TF2B), 茶黄素-3,3′-没食子酸酯(Theaflavin-3,3′-digallate,TFDG),新茶黄 素(Neotheaflavin,NEO),异茶黄素(Isotheaflavin,ISO))进行 比较,通过1μM和10μM的TFBG或其类似衍生物TF,TF2A, TF2B,TFDG,NEO,ISO单独地和与50.0ug/mL赫赛汀联合处理胃癌细胞SNU-215来进行MTT细胞增殖实验。结果显示TFBG增敏赫 赛汀的能力显著强于其它药物(图7)。
实施例6:茶黄素-3,3′-双没食子酸增强赫赛汀在乳腺癌中的治疗 效果
将赫塞汀与茶黄素-3,3′-双没食子酸联合处理HER2阳性的乳腺 癌细胞SKBR3之后,进行MTT细胞增殖实验以检测药物对乳腺癌细胞的抑制作用。结果显示,1μM的TFBG和10μM的TFBG均 能够显著促进赫塞汀抑制乳腺癌细胞增殖的能力,证明TFBG同样 能够增强赫赛汀在乳腺癌中的治疗效果(图8)。
Claims (3)
1.SHCBP1抑制剂和赫赛汀联合用于制备用于治疗HER2阳性癌症的组合物的用途;所述HER2阳性癌症选自HER2阳性胃癌和HER2阳性乳腺癌;所述SHCBP1抑制剂选自RNA干扰试剂、茶黄素-3-没食子酸酯和茶黄素-3,3′-双没食子酸;所述RNA干扰试剂为SEQ ID NO:1和2所示的shRNA。
2.一种用于治疗HER2阳性癌症的组合物,其包含SHCBP1抑制剂和赫赛汀;所述HER2阳性癌症为HER2阳性胃癌和HER2阳性乳腺癌;所述SHCBP1抑制剂选自RNA干扰试剂、茶黄素-3-没食子酸酯和茶黄素-3,3′-双没食子酸;所述RNA干扰试剂为SEQ ID NO:1和2所示的shRNA。
3.一种用于治疗HER2阳性癌症的试剂盒,其包含SHCBP1抑制剂和赫赛汀;所述HER2阳性癌症为HER2阳性胃癌和HER2阳性乳腺癌;所述SHCBP1抑制剂选自RNA干扰试剂、茶黄素-3-没食子酸酯和茶黄素-3,3′-双没食子酸;所述RNA干扰试剂为SEQ ID NO:1和2所示的shRNA。
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