CN117018204A - 一种治疗癌症的组合物及其应用和药物 - Google Patents
一种治疗癌症的组合物及其应用和药物 Download PDFInfo
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Abstract
本发明涉及医药技术领域,特别涉及一种治疗癌症的组合物及其应用和药物。该组合物包含SGLT1抑制剂和VEGFR2抑制剂。本发明发现SGLT1与VEGFR2具有相互作用并促进肿瘤的发生发展;本发明还发现靶向VEGFR2的抑制剂与SGLT1抑制剂的组合物具有协同抗肿瘤效应,可将靶向VEGFR2和SGLT1的抑制剂组合物用于癌症治疗。
Description
本申请为申请日为2020年07月06日,申请号为202010641456.1,发明创造名称为“一种治疗癌症的组合物及其应用和药物”的分案申请。
技术领域
本发明涉及医药技术领域,特别涉及一种治疗癌症的组合物及其应用和药物。
背景技术
恶性肿瘤是当今社会威胁人类生命的主要疾病之一。肿瘤的生长和侵袭需要诱导新生血管形成。诱导新生血管形成最重要的因子为血管内皮生长因子(VEGF),肿瘤细胞分泌的VEGF结合血管内皮细胞的受体(VEGFR)促进血管内皮细胞增殖,分裂形成新生血管促进肿瘤生长(Leung DW,Cachianes G,Kuang WJ,GoeddelDV,Ferrara N.Vascularendothelialgrowth factor is a secreted angiogenic mitogen.Science.1989;246:1306-–1309.Tischer E,et al.Vascular endothelialgrowth factor:a new member ofthe platelet-derived growth factor gene family.Biochem Biophys ResCommun.1989;165:1198-–1206.)。因而通过小分子靶向VEGFR酪氨酸激酶活性,抑制肿瘤新生血管形成,饿死肿瘤成为近年来肿瘤治疗的新途径。然而,通过受体酪氨酸激酶的小分子抑制剂靶向VEGFR并未产生令人满意的治疗功效。各种人恶性肿瘤的总体应答率较低,很快形成耐药性等问题亟需解决。
VEGFR家族主要有三个成员分别为VEGFR1、VEGFR2和VEGFR3,其中VEGFR2主要介导血管内皮细胞的生长。近年来的研究表明VEGFR2还在某些肿瘤细胞中高表达,因而肿瘤细胞分泌的VEGF在诱导新生血管形成的同时还以自分泌或旁分泌的形式作用于肿瘤细胞自身或者临近肿瘤细胞,间质细胞促进肿瘤干细胞形成以及免疫耐受微环境的形成(Kowanetz M,Ferrara N.Vascular endothelialgrowth factor signaling pathways:therapeutic perspective.Clin Cancer Res.2006;12:5018-–5022.Waldner MJ,etal.VEGF receptor signaling links inflammation and tumorigenesis incolitisassociated cancer.J Exp Med.2010;207:2855-–2868.HamerlikP,etal.Autocrine VEGF-–VEGFR2–-neuropilin-1signaling promotes glioma stem-likecell viability and tumor growth.J Exp Med.2012;209:507–-520.)。而VEGFR结合配体后促进肿瘤细胞自身的增殖,存活以及癌症的发展的具体机制还知之甚少。
肿瘤细胞不同于正常细胞的一个标志为癌细胞即便在氧气充足的条件下也优先使用有氧糖酵解来为肿瘤细胞提供能量。有氧糖酵解相比于氧化磷酸化产能效率低很多,这就需要肿瘤细胞转运葡萄糖的能力显著增强(Hanahan D et al,Hallmarks of cancer:the next generation,Cell,144(5):646-674(2011),这通过过表达质膜转运蛋白来实现(Ganapathy V,et al,Nutrient transporters in cancer:relevance to Warburghypothesis and beyond,Pharmacology&Therapeutics 121(1):29-40(2009)。葡萄糖共转运蛋白1(SGLT1)为主动的葡萄糖转运蛋白,其依靠细胞外钠浓度将葡萄糖转运至细胞而不依赖于葡萄糖浓度(Wright EM,et al,Biology of human sodium glucosetransporters,Physiological Reviews,91(2):733-794(2011))。研究表明SGLT1在多种癌症中高表达且与癌症的不良预后相关,所述癌症包括卵巢癌、口腔鳞状细胞癌、结直肠癌、胰腺癌和前列腺癌SGLT1可以结合并稳定EGFR从而促进肿瘤细胞的生长,增殖(J,Vrhovac/>I,Gajski G,/>J,GarajVrhovac V.Apigenin:A dietaryflavonoid with diverse anticancer properties.Cancer Lett 2018;413:11-22.Koepsell H.The Na+-D-glucose cotransporters SGLT1 and SGLT2 are targetsfor the treatment of diabetes and cancer.Pharmacol Ther 2017;170:148-–65.Yamazaki Y,Harada S,Tokuyama S.Sodium–glucose transporter as a noveltherapeutic target in disease.Eur J of Pharmacol 2018;822:25–31)。
目前,还未见将SGLT1抑制剂与VEGFR2抑制剂组合使用用于解决本领域治疗耐受VEGFR酪氨酸激酶抑制剂的癌症的报道。
发明内容
有鉴于此,本发明提供了一种治疗癌症的组合物及其应用和药物。本发明发现SGLT1与VEGFR2具有相互作用并促进肿瘤的发生发展,靶向VEGFR2的抑制剂与SGLT1抑制剂的组合物具有协同抗肿瘤效应。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了一种组合物,其包含钠/葡萄糖共转运蛋白1(SGLT1)抑制剂和血管内皮细胞生长因子受体(VEGFR)抑制剂。优选地,活性成分由SGLT1抑制剂和VEGFR2抑制剂组成。
作为优选,SGLT1抑制剂选自索格列净、米格列净(Mizagliflozin)、KGA-2727、卡那列嗪、达格列嗪中至少一种。但并不限于此,本领域技术人员认为可行的SGLT1抑制剂均在本发明保护范围之内。
作为优选,SGLT1抑制剂的给药剂量为1~100mg/kg。
优选地,SGLT1抑制剂的给药剂量为10~50mg/kg。
作为优选,VEGFR2抑制剂选自阿帕替尼、阿昔替尼(Axitinib)、尼达尼布(Nintedanib,BIBF 1120)、西地尼布(Cediranib,AZD2171)、盐酸帕唑帕尼(PazopanibHCl,GW786034HCl)、苹果酸舒尼替尼(Sunitinib Malate)、布立尼布(Brivanib,BMS-540215)、卡博替尼(Cabozantinib(XL184,BMS-907351)、丙氨酸布立尼布(BrivanibAlaninate,BMS-582664)、乐伐替尼(Lenvatinib,E7080)、瑞戈非尼(Regorafenib,BAY 73-4506)、ENMD-2076、替沃扎尼(Tivozanib,AV-951)、帕纳替尼(Ponatinib,AP24534)、ENMD-2076酒石酸盐(ENMD-2076L-(+)-Tartaric acid)、替拉替尼(Telatinib)、花旗松素(Taxifolin,Dihydroquercetin)、帕唑帕尼(Pazopanib)、苹果酸卡博替尼(Cabozantinibmalate,XL184)、维生素E(Vitamin E)、瑞戈非尼水合物(Regorafenib Monohydrate)、尼达尼布乙磺酸盐(Nintedanib Ethanesulfonate Salt)、乐伐替尼甲磺酸盐(lenvatinibMesylate)、西地尼布马来酸盐(Cediranib Maleate)、呋喹替尼(Fruquintinib)、4-[(1E)-2-[5-[(1R)-1-(3,5-二氯-4-吡啶基)乙氧基]-1H-吲唑-3-基]乙烯基]-1H-吡唑-1-乙醇(LY2874455)、舒尼替尼(Sunitinib)、西特拉瓦替尼(Sitravatinib,MGCD516)、安罗替尼(Anlotinib(AL3818)dihydrochloride)、索拉非尼、凡德他尼以及靶向VEGFR的单抗等中的至少一种。
靶向VEGFR的单抗如贝伐单抗,但并不限于此,本领域技术人员认为可行的靶向VEGFR的单抗均在本发明保护范围之内。
作为优选,VEGFR2抑制剂的给药剂量为10~500mg/kg。
优选地,VEGFR2抑制剂的给药剂量为10~100mg/kg。
本发明还提供了该组合物在制备治疗癌症的药物中的应用。
作为优选,癌症包括:膀胱癌、血癌、骨癌、脑癌、乳腺癌、中枢神经系统癌症、宫颈癌、结肠癌、子宫内膜癌、食管癌、胆囊癌、胃肠道癌、外生殖器癌、泌尿生殖道癌、头癌、肾癌、喉癌、肝癌、肺癌、肌肉组织癌症、颈癌、口腔或鼻黏膜癌、卵巢癌、胰腺癌、前列腺癌、皮肤癌、脾癌、小肠癌、大肠癌、胃癌、睾丸癌和/或甲状腺癌。
本发明还提供了一种治疗癌症的药物,该药物包括上述组合物。
作为优选,药物的给药方式为口服给药,其剂型包括颗粒剂、丸剂、散剂、片剂、胶囊剂、口服液或糖浆剂。
作为优选,药物的给药方式为注射给药,其剂型包括注射液或注射粉针剂。
本发明提供了一种治疗癌症的组合物及其应用和药物。该组合物包含SGLT1抑制剂和VEGFR2抑制剂。本发明具有的技术效果为:
本发明发现SGLT1与VEGFR2具有相互作用并促进肿瘤的发生发展,且这种相互作用对彼此的功能发挥具有重要作用,敲低VEGFR2不但会影响肿瘤细胞的增殖以及生长信号的转到同时也会影响SGLT1功能,反之敲低SGLT1不但影响癌细胞在低糖条件下的生存也会影响VEGFR2信号通路以及细胞的增殖;
本发明还发现靶向VEGFR2的抑制剂与SGLT1抑制剂的组合物具有协同抗肿瘤效应,可将靶向VEGFR2和SGLT1的抑制剂组合物用于癌症治疗。
附图说明
图1示VEGFR2与SGLT1高表达与肝癌、结直肠癌患者不良预后相关;其中,1A为VEGFR2高表达与肝癌患者预后的关系,1B为VEGFR2高表达与结直肠癌患者预后关系,1C为SGLT1高表达与肝癌患者预后的关系,1D为SGLT1高表达与结直肠癌患者预后关系;
图2示VEGFR2与SGLT1在肝癌和结直肠癌中具有正相关性;其中,2A为VEGFR2与SGLT1在肝癌中的表达具有正相关性,2B为VEGFR2与SGLT1在结直肠癌中的表达具有正相关性;
图3示肝癌细胞系中敲除VEGFR2以及SGLT1损伤细胞在裸鼠上的致瘤性;
图4示敲低SGLT1损伤VEGFR2信号通路,本发明以p-ERK1/2为标志物指示VEGFR2信号通路强度;
图5示敲低VEGFR2和SGLT1增加肝癌细胞系Hep3B对阿帕替尼的敏感性;
图6示敲低VEGFR2和SGLT1增加Hep3B细胞对葡萄糖饥饿的敏感性;
图7示VEGFR2与SGLT1存在蛋白之间的相互作用;
图8示VEGFR2抑制剂以及SGLT1抑制剂处理肝癌细胞系HepG2;
图9a示VEGFR2抑制剂以及SGLT1抑制剂处理结直肠癌细胞系SW620;
图9b示VEGFR2抑制剂以及SGLT1抑制剂处理宫颈癌细胞系HeLa;
图9c示VEGFR2抑制剂以及SGLT1抑制剂处理卵巢癌细胞系SKOV3;
图9d示VEGFR2抑制剂以及SGLT1抑制剂处理胃癌细胞系NGC27;
图9e示VEGFR2抑制剂以及SGLT1抑制剂处理结胆管癌细胞系RBE;
图9f示VEGFR2抑制剂以及SGLT1抑制剂处理结食管癌细胞系KYSE30;
图10示VEGFR2抑制剂以及SGLT1抑制剂治疗肝癌裸鼠移植瘤药效,10A为给药结束后解剖各组肿瘤大观图;10B为给药结束后各组肿瘤重量图;
图11-1至图11-30分别示阿昔替尼(图11-1)、尼达尼布(图11-2)、西地尼布(图11-3)、盐酸帕唑帕尼(图11-4)、苹果酸舒尼替尼(图11-5)、布立尼布(图11-6)、卡博替尼(图11-7)、丙氨酸布立尼布(图11-8)、乐伐替尼(图11-9)、瑞戈非尼(图11-10)、ENMD-2076(图11-11)、替沃扎尼(图11-12)、帕纳替尼(图11-13)、ENMD-2076酒石酸盐(图11-14)、替拉替尼(图11-15)、花旗松素(图11-16)、帕唑帕尼(图11-17)、苹果酸卡博替尼(图11-18)、维生素E(图11-19)、瑞戈非尼水合物(图11-20)、尼达尼布乙磺酸盐(图11-21)、乐伐替尼甲磺酸盐(图11-22)、西地尼布马来酸盐(图11-23)、4-[(1E)-2-[5-[(1R)-1-(3,5-二氯-4-吡啶基)乙氧基]-1H-吲唑-3-基]乙烯基]-1H-吡唑-1-乙醇(图11-24)、舒尼替尼(图11-25)、西特拉瓦替尼(图11-26)、安罗替尼(图11-27)、索拉非尼(图11-28)、凡德他尼(图11-29)、呋喹替尼(11-30)与SGLT1抑制剂索格列净联用的肿瘤抑制效果。
具体实施方式
本发明公开了一种治疗癌症的组合物及其应用和药物,本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合,来实现和应用本发明技术。
经TCGA数据分析恶性肿瘤的不良预后与血管内皮生长因子受体2(VEGFR2)以及钠/葡萄糖共转运蛋白1(SGLT1)的过表达相关。所述癌症包括肝癌、乳腺癌、结直肠癌。本发明发现在癌细胞中VEGFR与SGLT1相互作用并互相影响彼此功能。
通过以下大量细节描述,在本发明中已经确定了如下实施方案:
1)在肝癌和乳腺癌中VEGFR2、SGLT1、SGLT2的高表达对癌症患者的不良预后的影响;
2)SGLT1对VEGFR2信号通路的作用;
3)SGLT1在肝癌细胞中对VEGFR2酪氨酸抑制剂的敏感性的抑制作用;
4)VEGFR2对SGLT1功能正常发挥的作用;
5)VEGFR2与SGLT1之间的相互作用;
6)VEGFR2与SGLT1抑制剂单药以及组合物对肿瘤细胞的作用;
7)VEGFR2与SGLT1抑制剂单药以及组合物对裸鼠移植瘤的作用。
本发明试验结果如下:
(1)VEGFR2和SGLT1高表达正相关且与癌症患者不良预后相关
在一个实施方案中,肝癌、乳腺癌患者的VEGFR2以及SGLT1高表达与不良预后正相关,并且VEGFR2的高表达与SGLT1的高表达也存在正相关性。在另一个实施方案中敲低SGLT1损伤VEGFR2信号的传导时增强了相应肿瘤细胞系对VEGFR2酪氨酸激酶活性抑制剂的敏感性,又在另一个实施方案中敲低VEGFR2同样损伤了SGLT1功能,并且SGLT1与VEGFR2之间还存在直接相互作用。所有这些数据表明,VEGFR2表达与血管内皮细胞可以促进新生血管生成促进肿瘤发展,其表达在肿瘤细胞自身则会通过与SGLT1相互作用调控肿瘤细胞的能量代谢和增殖信号。因此,在实施方案中,SGLT1为参与VEGFR2的功能的蛋白质,以及VEGFR2-SGLT1相互作用可为癌症治疗的新型靶标。
已有研究表明,VEGFR2除了在血管内皮细胞中高表达,还在某些癌症细胞自身高表达,SGLT1已明确在前列腺癌中高表达(HuangJ,et al.Prognostic significance andpotential therapeutic target of VEGFR2 in hepatocellular carcinoma.J ClinPathol.2011;64:343–348.Blessing A,et al.Sodium/Glucose Co-transporter1Expression Increases in Human Diseased Prostate,J.Cancer Sci.Ther.4(9):306-312(2012))。本发明通过挖掘TCGA数据库将VEGFR2以及SGLT1、SGLT2的表达量与肝癌和结直肠癌患者的总生存期进行生存分析发现,VEGFR2以及SGLT1的高表达与肝癌、结直肠癌患者的不良预后正相关,而SGLT2则无此相关性。如图1A、1B所示,仅以举例方式证明VEGFR2以及SGLT1的高表达与这两种癌症患者的不良预后相关,说明二者在肿瘤细胞自身的表达中与预后的关系。这并不能限制为本发明实施方案的组合物仅限于肝癌和结直肠癌。例如在另一个实施方案中组合物即对宫颈癌,卵巢癌,胃癌,食管癌,胆管癌细胞系具有显著抑制作用,如图9b-9f。
进一步的在另一个实施方案中,本发明通过皮尔森检验对从TCGA数据库中获得的VEGFR2和SGLT1、SGLT2在肝癌和乳腺癌肿瘤患者中的表达量数据进行关联性分析发现VEGFR2与SGLT1的表达之间存在正相关性,而与SGLT2之间的表达量无相关性,如图2A、2B所示。这说明VEGFR2与SGLT1两者功能很可能具有一定关联性。为了验证TCGA数据显示的VEGFR2以及SGLT1对肝癌的重要性,本发明在肝癌细胞系Hep3B中分别敲低VEGFR2以及SGLT1并进行裸鼠移植瘤实验,发现敲低VEGFR2和SGLT1的细胞系裸鼠移植瘤成瘤性显著减弱,说明这两个基因对肿瘤的发生发展起重要作用,如图3所示。
(2)VEGFR2与SGLT1对彼此功能相互影响
根据本发明前述数据分析得出的推论,在一个实施方案中,本发明利用慢病毒感染细胞,用shRNA技术在肝癌Hep3B细胞中分别敲低VEGFR2、SGLT1和SGLT2来验证彼此之间功能的相互影响。ERK1/2是VEGFR2酪氨酸激酶活性激活后的一个下游分子,VEGFR2激活后会引起ERK1/2的磷酸化(Giatromanolaki A,et al.Hypoxia and activated VEGF/receptor pathway in multiple myeloma.Anticancer Res.2010;30:2831–2836.)。在一个实施方案中,本发明评价敲低VEGFR2、SGLT1和SGLT2后磷酸化ERK1/2的强度来判断敲低SGLT1/2是否影响VEGFR2信号。结果如图4所示,敲低SGLT1与敲低VEGFR2一致都会诱导ERK1/2磷酸化强度下调,而敲低SGLT2则无此影响。若敲低SGLT1引起了VEGFR2信号通路的损伤,那么相应的敲低SGLT1的细胞会与敲低VEGFR2的细胞一样对VEGFR2抑制剂更敏感,本发明仅以VEGFR2抑制剂Apatinib为例,将对照细胞以及敲低VEGFR2、SGLT1和SGLT2的各个细胞系铺于96孔板,加入不同浓度的Apatinib处理各组细胞,利用MTT法测出Apatinib对各组细胞的IC50值。结果如图5所示,敲低SGLT1与敲低VEGFR2一致将Apatinib的IC50值降低了一半以上,而敲低SGLT2则无此效果。众所周知SGLT1为细胞逆葡萄糖浓度梯度吸收外界环境葡萄糖供能(Thorens B,Mueckler M.Glucose transporters in the 21stCentury.Am J Physiol-Endoc M 2010;298:E141-5.doi:10.1152/ajpendo.00712.2009)。因而敲低SGLT1的肿瘤细胞在低糖培养条件下会因缺少葡萄糖供应而优先死亡。在本发明的一个实施案例中采用低糖培养基培养敲低VEGFR2、SGLT1和SGLT2的肝癌Hep3B细胞,在光镜下每隔一段时间观察一次细胞状态,结果如图6所示,敲低VEGFR2与敲低SGLT1一致可以降低细胞对葡萄糖饥饿的耐受能力,而敲低SGLT2则并无明显影响。综合以上本发明首次发现在VEGFR2与SGLT1这两个分子之间存在功能上的相互影响。
值得提出的是,本发明仅以肝癌Hep3B细胞为例敲低各基因评价他们之间的相互影响,本发明所得结论不应受限于此癌种和细胞系。
(3)VEGFR2与SGLT1存在分子间的相互作用
基于以上本发明首次发现的VEGFR2和SGLT1之间功能的相互影响,本发明在实施方案中,通过免疫共沉淀实验进一步确定VEGFR2与SGLT1存在分子间的相互作用。用表达Flag标记的SGLT1的质粒单独转染或与指定的GFP标记的VEGFR2载体在无血清DMEM培养基中混合并加入转染试剂PEI后一起转染HEK293T细胞。在转染6小时之后更换为10%血清的培养基,更换培养基之后24小时,弃去培养基,用10毫升1×磷酸盐缓冲液中洗涤(PBS)将细胞吹起并1500转离心,弃去上清所得细胞团沉淀加入补充有蛋白酶抑制剂混合物的RIPA缓冲液(50mMTris-HCl,pH 8.0,具有150mM氯化钠,1.0%Igepal CA-630(NP-40),0.5%脱氧胆酸钠和0.1%十二烷基硫酸钠)并在摇床于4℃下裂解30分钟。然后,将细胞裂解物以12000×rpm离心10分钟。将上清液加入偶联有Flag抗体的M2微珠于4℃孵育过夜。然后,将样品离心,用RIPA缓冲液洗涤三次,在Laemmle缓冲液(Biorad,CA)中煮沸,用8%SDS PAGE胶进行蛋白质印记分析。IP=免疫沉淀,IB=免疫印迹,以及Input=在用于免疫沉淀的HEK293全细胞裂解物中指定的外源蛋白的表达水平。结果如图7所示。
(4)通过SGLT1抑制剂抑制SGLT1使肝癌、结直肠癌细胞对VEGFR2抑制剂敏感。
图8、图9仅以举例的方式说明了在肝癌HepG2细胞系,结直肠癌细胞系SW620以及其他5种常见癌症细胞系中评价VEGFR2抑制剂阿帕替尼以及SGLT1抑制剂索格列净单药以及组合物的IC50值。基于这些结果,在一个实施方案中,SGLT1和VEGFR2功能的共抑制可更有效地抑制癌细胞生长。在又一实施方案中,以索格列净为例的SGLT1抑制剂可显著地使肝癌细胞系Hep3B的裸鼠移植瘤对阿帕替尼的生长抑制作用敏感,如图10所示。在实施方案中,可将索格列净等SGLT1抑制剂类化合物通过静脉内、口服于患者以治疗癌症。在又一实施方案中,可将索格列净等SGLT1抑制剂类化合物与VEGFR2酪氨酸激酶抑制剂一起施用于患者以治疗癌症。
本发明提供的治疗癌症的组合物及其应用和药物中所用试剂或仪器均可由市场购得。
下面结合实施例,进一步阐述本发明:
实施例1
1、细胞和试剂
本发明所用肝癌细胞系Hep3B、HepG2;结直肠癌细胞系SW620、HCT116、SW480、LOVO、HT29、DLD1;宫颈癌HeLa;卵巢癌SKOV3;胃癌NGC27;胆管癌RBE;食管癌KYSE30以及HEK293T细胞系均从美国典型培养物保藏中心(ATCC)并在含有5%CO2的37℃孵箱中培养,所述细胞系的维持培养基为补充有10%胎牛血清(Gibico)和1%青霉素/链霉素(Gibico)的DMEM或者RPMI 1640(Gibico)中。小鼠抗Flag标签抗体(F3165),Flag抗体欧联M2微珠购自Sigma-Aldrich(St.Louis,MO),小鼠抗GFP标签抗体、兔GAPDH内参抗体以及辣根过氧化物酶标记的抗兔和小鼠二抗购自博奥龙公司。Sotagliflozin、阿帕替尼和乐伐替尼均获自Selleckchem(Houston,TX)。抗pERK的抗体(4370)获自CellSignaling(Danvers,MA)。MTT试剂盒(目录号30-1010K)获自ATCC。
2、质粒构建
将人野生型VEGFR克隆至PEGFP-N1载体,人野生型SGLT1序列克隆至PCDH-EF1-CMV载体中。将靶向如下Sglt1-1 shRNA序列:5’-AGGAGAGCCTATGACCTATTT-3’;Sglt1-2 shRNA序列:5’-GCCTGATG CTATCAGTCATGC-3’;Sglt2-1 shRNA序列:5’-GCATATTTCCTGCTGGTCATT-3’;Sglt2-2 shRNA序列:5’-GGTCATCACGATGCCACAGTA-3’;Vegfr2-1 shRNA序列:5’-GATGAAAGTTACCAGTCTATT-3’;Vegfr2-2 shRNA序列:5’-GCTGACATGTACGGTCTATGC-3’序列的shRNA构建到pLVX-shRNA2-puro载体用于后续包被慢病毒构建SGLT1、SGLT2、VEGFR2敲低的细胞系。所有载体通过测序验证为正确质粒。
3、瞬时转染和免疫共沉淀
用表达Flag标记的SGLT1的质粒单独转染或与指定的GFP标记的VEGFR2载体在无血清DMEM培养基中混合并加入转染试剂PEI后一起转染HEK293T细胞。在转染6小时之后更换为10%血清的培养基,更换培养基之后24小时,弃去培养基,用10毫升1×磷酸盐缓冲液中洗涤(PBS)将细胞吹起并1500转离心,弃去上清所得细胞团沉淀加入补充有蛋白酶抑制剂混合物的RIPA缓冲液(50mMTris-HCl,pH 8.0,具有150mM氯化钠,1.0%Igepal CA-630(NP-40),0.5%脱氧胆酸钠和0.1%十二烷基硫酸钠)并在摇床于4℃下裂解30分钟。然后,将细胞裂解物以12000×rpm离心10分钟。将上清液加入偶联有Flag抗体的M2微珠于4℃孵育过夜。然后,将样品离心,用RIPA缓冲液洗涤三次,在Laemmle缓冲液(Biorad,CA)中煮沸,用8%SDS PAGE胶进行蛋白质印记分析。
4、蛋白质印记分析
对于蛋白质印记(Western blot)分析,将细胞用恰当体积的RIPA缓冲液(150mMNaCl,50mM Tris-HCl,pH7.4,0.1%SDS,1%TritonX-100,1mM EDTA,1mMPMSF,1%脱氧胆酸钠,1mM NaF,1mM Na3VO4,于去离子水中)在4℃条件下或者冰上裂解30分钟以上。12000×rpm离心10分钟,上清用BCA试剂盒(Thermo)测定蛋白浓度后加入5×loadingBuffer在100℃煮沸10分钟。短暂离心后,将样品通过10%SDS-PAGE进行电泳分离后转移至PVDF膜,随后用5%脱脂奶粉封闭一小时以上,然后在4℃下与一抗在最佳浓度过夜孵育。将膜用0.1%PBST(1×TBS,0.1%吐温-20)洗涤3次,每次10分钟,然后与二抗在室温孵育1小时。通过增强化学发光使信号可视化。
5、细胞生长测定
根据生产厂家提供的方案,检测原理为活细胞线粒体中的琥珀酸脱氢酶能使外源性MTT还原为水不溶性的蓝紫色结晶甲臜(Formazan)并沉积在细胞中,而死细胞无此功能。二甲基亚砜(DMSO)能溶解细胞中的甲臜,用酶联免疫检测仪在570nm波长处测定其光吸收值,可间接反映活细胞数量。在96孔板中通过3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四氮唑(MTT)测定来确定细胞生长。具体而言,细胞消化计数,将细胞重悬浮成每200μL培养基含5000个细胞的体系,接种在在96孔板的每个孔中。第二天,将培养基用含有不同浓度的索格列净,阿帕替尼,乐伐替尼以及它们之间的组合物的培养基更换。在与药物孵育48或72小时之后,将20μL MTT试剂加入至每个孔中并孵育2小时。在弃去培养基之后,将细胞中的甲臜沉淀物溶解在100μL DMSO中。通过酶标仪在570nm下测量吸光度。在每组中使用一式四份样品。
6、裸鼠移植瘤药效评价
用10%血清DMEM培养基培养Hep3B细胞,待细胞生长至对数期,消化计数,根据本发明前期条件摸索发现Hep3B细胞5*10e6个细胞每只腋下皮下接种Balbc裸鼠(购自维通利华)后可在21天左右形成移植瘤。故本发明采用5*10e6个细胞每只裸鼠剂量,在21天左右待肿瘤生长至平均体积100mm3开始分组给药。给药分为溶剂对照组,口服阿帕替尼50mg/kg给药组,腹腔注射索格列净20mg/kg给药组以及同时口服阿帕替尼50mg/kg和腹腔注射索格列净20mg/kg联合用药组。给药周期为每隔一天一次,并于每周二、周五测量肿瘤体积大小,按照公式V=a*b2/2进行肿瘤体积计算(a为测量肿瘤长径,b为测量肿瘤短径)。将测量结果利用Graphpad prism 5进行作图并统计分析。
7、统计分析
将学生t检验用于评估索格列净,阿帕替尼,乐伐替尼等SGLT1和VEGFR2抑制剂不同浓度,不同组合条件处理下的细胞的生长差异以及裸鼠移植瘤生长差异。P值小于0.05被定义为具有统计显著性。
8、试验结果
图1:1A,1B通过对TCGA数据库分析肝癌、结直肠癌患者癌组织中的VEGFR2表达高低与患者总生存期的关联性得出VEGFR2高表达的患者总生存期更短;1C,1D通过对TCGA数据库分析肝癌、结直肠癌患者癌组织中的SGLT1表达高低与患者总生存期的关联性得出SGLT1高表达的患者总生存期更短;证明VEGFR2以及SGLT1的高表达与这两种癌症患者的不良预后相关,说明二者在肿瘤细胞自身的表达中与预后的关系。
图2:2A通过皮尔森检验进一步分析TCGA数据库中肝癌患者癌组织中VEGFR2的表达水平与SGLT1的表达水平具有正向关联性;2B通过皮尔森检验进一步分析TCGA数据库中结直肠癌患者癌组织中VEGFR2的表达水平与SGLT1的表达水平具有正向关联性。说明VEGFR2与SGLT1两者功能很可能具有一定关联性。
图3:肝癌细胞系中敲除VEGFR2以及SGLT1损伤细胞在裸鼠上的致瘤性;说明VEGFR2和SGLT1这两个基因对肿瘤的发生发展起重要作用。
图4:利用shRNA技术从肝癌细胞系Hep3B中敲低SGLT1、SGLT2以及VEGFR2后,利用Western检测VEGFR2下游信号通路ERK1/2的磷酸化强度变化,敲低SGLT1与敲低VEGFR2一致可以降低ERK1/2的磷酸化强度,而敲低SGLT2则无这种效果。表明敲低SGLT1与敲低VEGFR2一致都会诱导ERK1/2磷酸化强度下调,而敲低SGLT2则无此影响。
图5:利用shRNA技术从肝癌细胞系Hep3B中敲低SGLT1、SGLT2以及VEGFR2后,分别用VEGFR2抑制剂Apatinib处理对照组细胞以及敲低VEGFR2、SGLT1以及SGLT2的细胞检测不同浓度apatinib对各细胞系的生长抑制,并计算半数抑制剂量IC50值;敲低SGLT1与敲低VEGFR2一致可以降低apatinib的IC50值,而敲低SGLT2则无这种效果。
图6:利用shRNA技术从肝癌细胞系Hep3B中敲低SGLT1、SGLT2以及VEGFR2后,分别用低糖DMEM培养基处理对照组细胞以及敲低VEGFR2、SGLT1以及SGLT2的细胞检测各细胞系对葡萄糖饥饿的耐受能力;敲低VEGFR2与敲低SGLT1一致可以降低细胞对葡萄糖饥饿的耐受能力,而敲低SGLT2则并无明显影响。
图7:VEGFR2与SGLT1存在蛋白之间相互作用;利用免疫共沉淀的方法将FLAG标签的SGLT1与无标签的VEGFR2载体共转染293T细胞,24小时后裂解细胞,加入FLAG珠子结合5小时,利用VEGFR2抗体和Flag抗体进行Western检测。结果表明,VEGFR2与SGLT1存在蛋白之间相互作用。
图8:使用VEGFR2抑制剂以及SGLT1抑制剂处理肝癌细胞系HepG2,利用MTT法分别测量VEGFR2抑制剂以及SGLT1抑制剂单药以及二者不同剂量组合物联合用药VEGFR2抑制剂的IC50值。证明组合物对肝癌细胞系具有显著抑制作用。
图9:图9a示VEGFR2抑制剂以及SGLT1抑制剂处理结直肠癌细胞系SW620;图9b示VEGFR2抑制剂以及SGLT1抑制剂处理宫颈癌细胞系HeLa;图9c示VEGFR2抑制剂以及SGLT1抑制剂处理卵巢癌细胞系SKOV3;图9d示VEGFR2抑制剂以及SGLT1抑制剂处理胃癌细胞系NGC27;图9e示VEGFR2抑制剂以及SGLT1抑制剂处理结胆管癌细胞系RBE;图9f示VEGFR2抑制剂以及SGLT1抑制剂处理结食管癌细胞系KYSE30;证明组合物对结直肠癌细胞系、宫颈癌细胞系、卵巢癌细胞系、胃癌细胞系、结胆管癌细胞系、结食管癌细胞系具有显著抑制作用。
图10:利用VEGFR2抑制剂以及SGLT1抑制剂处理肝癌细胞系Hep3B的裸鼠移植瘤,检测VEGFR2抑制剂(50mg/kg)以及SGLT1抑制剂(20mg/kg)单药以及二者组合物联合用药对肿瘤生长的抑制效果。证明组合物对肿瘤生长具有显著抑制作用。
实施例2
在图8,图9,图10以阿帕替尼作为代表的VEGFR2抑制剂联用SGLT1抑制剂具有体内体外疗效,本发明利用肝癌细胞系进一步验证目前已经上临床和正在进行临床试验的所有VEGFR2抑制剂与SGLT1抑制剂联合用药的效果。结果显示阿昔替尼(Axitinib)(图11-1)、尼达尼布(Nintedanib,BIBF 1120)(图11-2)、西地尼布(Cediranib,AZD2171)(图11-3)、盐酸帕唑帕尼(Pazopanib HCl,GW786034HCl)(图11-4)、苹果酸舒尼替尼(Sunitinib Malate)(图11-5)、布立尼布(Brivanib,BMS-540215)(图11-6)、卡博替尼(Cabozantinib(XL184,BMS-907351)(图11-7)、丙氨酸布立尼布(Brivanib Alaninate,BMS-582664)(图11-8)、乐伐替尼(Lenvatinib,E7080)(图11-9)、瑞戈非尼(Regorafenib,BAY 73-4506)(图11-10)、ENMD-2076(图11-11)、替沃扎尼(Tivozanib,AV-951)(图11-12)、帕纳替尼(Ponatinib,AP24534)(图11-13)、ENMD-2076酒石酸盐(ENMD-2076L-(+)-Tartaric acid)(图11-14)、替拉替尼(Telatinib)(图11-15)、花旗松素(Taxifolin,Dihydroquercetin)(图11-16)、帕唑帕尼(Pazopanib)(图11-17)、苹果酸卡博替尼(Cabozantinib malate,XL184)(图11-18)、维生素E(Vitamin E)(图11-19)、瑞戈非尼水合物(Regorafenib Monohydrate)(图11-20)、尼达尼布乙磺酸盐(Nintedanib Ethanesulfonate Salt)(图11-21)、乐伐替尼甲磺酸盐(lenvatinib Mesylate)(图11-22)、西地尼布马来酸盐(Cediranib Maleate)(图11-23)、4-[(1E)-2-[5-[(1R)-1-(3,5-二氯-4-吡啶基)乙氧基]-1H-吲唑-3-基]乙烯基]-1H-吡唑-1-乙醇(LY2874455)(图11-24)、舒尼替尼(Sunitinib)(图11-25)、西特拉瓦替尼(Sitravatinib,MGCD516)(图11-26)、安罗替尼(Anlotinib(AL3818)dihydrochloride)(图11-27)、索拉非尼(图11-28)、凡德他尼(图11-29)、呋喹替尼(11-30)等药物与SGLT1抑制剂联用均具有较单药更好的肿瘤抑制效果。
结论
本发明发现SGLT1与VEGFR2具有相互作用,且这种相互作用对彼此的功能发挥具有重要作用,敲低VEGFR2不但会影响肿瘤细胞的增殖以及生长信号的转到同时也会影响SGLT1功能,反之敲低SGLT1不但影响癌细胞在低糖条件下的生存也会影响VEGFR2信号通路以及细胞的增殖。因此,VEGFR2抑制剂以及SGLT1抑制剂组成的组合物对肿瘤生长具有显著抑制作用,该组合物对肿瘤的抑制具有显著的协同增效作用。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (8)
1.一种组合物,其特征在于,包含钠/葡萄糖共转运蛋白1抑制剂和血管内皮细胞生长因子受体抑制剂;
所述钠/葡萄糖共转运蛋白抑制剂选自索格列净、米格列净、KGA-2727、卡那列嗪、达格列嗪中至少一种;
所述血管内皮细胞生长因子受体抑制剂选自阿昔替尼、尼达尼布、西地尼布、盐酸帕唑帕尼、苹果酸舒尼替尼、布立尼布、卡博替尼、丙氨酸布立尼布、乐伐替尼、瑞戈非尼、ENMD-2076、ENMD-2076酒石酸盐、替沃扎尼、帕纳替尼、呋喹替尼、替拉替尼、花旗松素、帕唑帕尼、苹果酸卡博替尼、维生素E、瑞戈非尼水合物、尼达尼布乙磺酸盐、乐伐替尼甲磺酸盐、西地尼布马来酸盐、4-[(1E)-2-[5-[(1R)-1-(3,5-二氯-4-吡啶基)乙氧基]-1H-吲唑-3-基]乙烯基]-1H-吡唑-1-乙醇、舒尼替尼、西特拉瓦替尼、安罗替尼、索拉非尼、凡德他尼以及靶向VEGFR的单抗类药物中的至少一种。
2.根据权利要求1所述的组合物,其特征在于,所述钠/葡萄糖共转运蛋白抑制剂的给药剂量为1~100mg/kg。
3.根据权利要求1所述的组合物,其特征在于,所述钠/葡萄糖共转运蛋白抑制剂的给药剂量为10~50mg/kg。
4.根据权利要求1所述的组合物,其特征在于,所述血管内皮细胞生长因子受体抑制剂的给药剂量为10~500mg/kg。
5.根据权利要求1至4中任一项所述的组合物,其特征在于,所述血管内皮细胞生长因子受体抑制剂的给药剂量为10~100mg/kg。
6.权利要求1至5中任一项所述组合物在制备治疗癌症的药物中的应用。
7.根据权利要求6所述的应用,其特征在于,所述癌症包括:膀胱癌、血癌、骨癌、脑癌、乳腺癌、中枢神经系统癌症、宫颈癌、结肠癌、子宫内膜癌、食管癌、胆囊癌、胃肠道癌、外生殖器癌、泌尿生殖道癌、头癌、肾癌、喉癌、肝癌、肺癌、肌肉组织癌症、颈癌、口腔或鼻黏膜癌、卵巢癌、胰腺癌、前列腺癌、皮肤癌、脾癌、小肠癌、大肠癌、胃癌、睾丸癌和/或甲状腺癌。
8.一种治疗癌症的药物,其特征在于,包括权利要求1至5中任一项所述的组合物。
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