CN110312709A - 包含表儿茶素和抗癌化合物的组合的组合物 - Google Patents

包含表儿茶素和抗癌化合物的组合的组合物 Download PDF

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CN110312709A
CN110312709A CN201780081834.1A CN201780081834A CN110312709A CN 110312709 A CN110312709 A CN 110312709A CN 201780081834 A CN201780081834 A CN 201780081834A CN 110312709 A CN110312709 A CN 110312709A
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epicatechin
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桑迪普·杜加尔
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Abstract

本发明披露了一种表儿茶素与抗癌化合物的稳定的新型协同组合。本发明还披露了一种包含表儿茶素与抗癌化合物的新型组合以及其他可药用的赋形剂的组合物。

Description

包含表儿茶素和抗癌化合物的组合的组合物
技术领域
本发明涉及表儿茶素和抗癌化合物的新型组合、以及包含该新型组合的组合物。
背景技术
癌症是人类最普遍的疾病之一，在人类死亡率和发病率中占比最高，导致每年死亡人数达数百万，并且还会降低患者的生活品质。癌症作为一类疾病的特点为异常的细胞生长，并且可能会入侵和/或扩散至身体的其他部分，并且全世界范围内所有癌症的发生率在增加。癌症的发生率一般涉及如下因素：遗传因素、暴露于特定毒素和已知的致癌物、特定的物质、饮食、诸如吸烟(烟草)之类的习惯等等。已经确定癌细胞内遗传和代谢途径的改变为疾病的原因。瓦伯格效应(Warburg effect)观察到大多数癌细胞主要通过糖酵解以及随后的乳酸发酵产生能量，而非如大多数正常细胞那样通过线粒体中的丙酮酸盐的氧化产生能量(Gatenby RA；Gillies RJ，Nature Reviews Cancer 4(11)：891-9，2004；Kim JW，Dang CV，Cancer Res.66(18)：8927-8930，2006)。后一过程是好氧的(使用氧)。通常，快速生长的恶性肿瘤细胞的糖酵解速率高达正常的原发组织的糖酵解速率的200倍；即使氧丰富，也会发生这种情况。Otto Warburg假设这种代谢的改变对于癌细胞而言是非常重要的[Warburg O，Science 123(3191)：309-314，1956]，该主张现在被称为瓦伯格效应。瓦伯格效应可仅仅是癌细胞中线粒体受损的结果，或者是对肿瘤内低氧环境的适应，或者是癌症基因由于参与细胞凋亡程序而关闭线粒体所致(这原本会杀死癌细胞)。瓦伯格效应也可以是与细胞增殖有关的效应。由于糖酵解提供了细胞增殖所需的大部分结构单元，因此癌细胞需要激活糖酵解以进行增殖。目前，认为致癌基因和肿瘤抑制基因的突变是造成恶性转化的原因，并且认为瓦伯格效应是这些突变的结果，而非诱因。[Bertram JS,Mol.AspectsMed.21(6):167-223,2000.Grandér D,Med.Oncol.15(1):20-26,1998]。同时发生的肥胖也是肿瘤发生的诱因(Oncogene.2016Dec 8；35(49):6271-6280)
目前，人们正深入研究抑制糖酵解的化合物作为抗癌剂，[Pelicano H,MartinDS,Xu RH,Huang P Oncogene 25(34):4633-4646,2006]包括SB-204990、2-脱氧-D-葡萄糖(2DG)、3-溴丙酮酸(3-BrPA、溴丙酮酸或溴丙酮酸盐)、3-BrOP、5-硫葡糖和和二氯乙酸(DCA)。在脑肿瘤临床前研究中，已成功将α-氰基-4-羟基肉桂酸用作代谢靶标，其中α-氰基-4-羟基肉桂酸是单羧酸转运蛋白(MCT；其防止乳酸在肿瘤中累积)的小分子抑制剂。二氯乙酸(DCA)是线粒体丙酮酸脱氢激酶的小分子抑制剂，其“下调”体外和体内的糖酵解，并且对于许多类型的癌症可能具有治疗益处。致癌基因和肿瘤抑制基因的突变也是造成恶性转化的原因。另一个影响癌细胞中的糖酵解途径的可能性是增强线粒体途径并促进氧化磷酸化。
因此，癌细胞在代谢方面和线粒体方面存在重大改变。因此，对癌细胞中的代谢途径/线粒体途径和致癌途径的干涉应具有更大的益处。
此外，治疗癌症的药物和药物组合物是患者可普遍获得的，这些药物和组合物通常剂量非常高且治疗持续时间长，这会导致患者产生各种副作用，并且一些药物会随着耐药性的形成而失效。因此，降低这些药物的剂量并缩短治疗持续时间将会在减少副作用的同时提高功效，从而为患者提供显著的益处。
据报道，存在于巧克力、茶叶、水果、植物和葡萄酒中的黄酮醇由于其抗氧化活性而被用于癌症的治疗中。例如：此前已报道儿茶素能够增强抗癌化合物(如多柔比星(阿霉素))的效果(Sugiyama and Sadzuka,1998,Can.Lett.133:19-26和Sadzuka等人，1998,Clin.Can.Res.4:153-156)。但是黄酮醇通常不会影响代谢途径和线粒体途径。初期研究证明表儿茶素、尤其是(-)-表儿茶素和(+)-表儿茶素(统称为“表儿茶素”)能够有效增强代谢途径和线粒体途径，并且其活性明显优于其他黄酮醇(参见PCT/US2012/040929)。
因此，本发明检验了表儿茶素与抗癌化合物联合的效果。
本发明的目的
本发明的目的是提供一种表儿茶素与抗癌化合物的稳定的新型协同组合，以及包含该新型组合的组合物。
发明内容
本发明披露了表儿茶素与抗癌化合物的稳定的新型协同组合。本发明还披露了包含表儿茶素与抗癌化合物的新型组合以及其他可药用的赋形剂的组合物。
附图说明
图1a示出了在基于HCT116细胞系诱导异种移植模型的结肠癌小鼠中，外消旋表儿茶素与PI3K/mTOR抑制剂化合物No.1004组合时的协同效果(口服)；
图1b示出了外消旋表儿茶素与PI3K/mTOR抑制剂化合物No.1004组合时，在减小肿瘤重量中的协同效果；
图2a示出了顺铂在抑制细胞生长中的效果；
图2b示出了表儿茶素在抑制A549中的效果；
图2c示出了等效线图解中所涉及的原理；
图2d示出了证实顺铂和(-)表儿茶素的协同效果的等效线图解；
图3示出了(-)表儿茶素和顺铂在诸如NCI-H1299和HCC-827之类的癌细胞系中的协同效果；并且
图4a和图4b示出了(-)表儿茶素和顺铂在细胞凋亡中的协同效果。
具体实施方式
本发明披露了表儿茶素与至少一种抗癌化合物的新型抗癌组合。
本发明的表儿茶素可选自由(+)表儿茶素、(-)表儿茶素、或者(+)表儿茶素和(-)表儿茶素的混合物组成的组。
表儿茶素在本发明的组合中的比例可在0.1％至99.9％到99.9％至0.1％的范围内变化，并且组合中的剩余成分可为抗癌化合物。本发明披露了表儿茶素的纯异构体、表儿茶素的混合物与抗癌化合物的稳定的新型协同组合。(+)表儿茶素:(-)表儿茶素的比例可在0.1:99.9至99.9:0.1的范围内变化。
本发明的表儿茶素可由天然来源得到或由合成获得。
本发明的抗癌化合物可选自由下列组成的组：烷基化抗肿瘤化合物，如环磷酰胺、亚硝基脲、醇磺酸盐；铂配位化合物，如顺铂、卡铂、奥沙利铂；抗代谢物，如氨甲喋呤、6-巯基嘌呤和5-氟尿嘧啶(5-FU)、吉西他滨；抗肿瘤抗生素，如阿霉素；微管抑制剂，如多西他赛、紫杉醇、拓扑替康、依托泊苷、依立替康、长春碱；生物化合物，如伊马替尼、拉帕替尼、舒尼替尼、索拉非尼、坦罗莫司；双膦酸盐，如伊班膦酸、唑来膦酸免疫治疗化合物；靶向抗癌治疗化合物和其他一般的化疗化合物，如由下列组成的组：选择性或非选择性的PI3激酶抑制剂、mTOR抑制剂、MEK抑制剂、Akt抑制剂、酪氨酸激酶抑制剂，如针对EGF受体的伊马替尼、埃罗替尼和吉非替尼；FGF、VEGF、PDGF的舒尼替尼抑制剂；ALK抑制剂、ABL、SCR、FLT3、KIT、MET抑制剂、BRAF抑制剂、Ilβ抑制剂、JAK1/2、JAK 3抑制剂、蛋白体抑制剂硼替佐米、其他生长因子抑制剂、RAS/RAF/MAPK途径抑制剂和其他信号转导抑制剂、多靶点激酶抑制剂、拓扑异构酶抑制剂、糖酵解抑制剂、组织蛋白酶B抑制剂、组蛋白脱乙酰基酶抑制剂等，其可单独使用或者与本领域技术人员已知的其他抗癌化合物组合使用。
优选地，本发明的抗癌化合物可选自含铂抗癌药物(如顺铂、卡铂或奥沙利铂)、化疗化合物(如PI3激酶/mTOR抑制剂)。
基于本发明的新型组合，抗癌化合物的含量比可为0.01至99.99。
本发明的抗癌化合物可为下表1中所列出的PI3激酶/mTOR抑制剂，或者可选自具有PI3激酶/mTOR的其他化合物。
表1：具有PI3K/mTOR活性的示意性化合物
在另一方面中，本发明披露了包含本发明的新型组合以及其他可药用的赋形剂的组合物。
本发明的组合物可配制为适合于口服施用、局部施用或肠胃外施用的剂型。
不受理论的限制，认为本发明所披露的表儿茶素和抗癌化合物的新型组合协同作用并极大增强了缓解各种癌症的效果以及癌症治疗的协同效果，降低了患者对抗癌组合产生耐药性的风险，降低了与肥胖相关的影响，诱导了癌细胞系的细胞凋亡，诱导了对于癌细胞的免疫应答，降低了瓦伯格效应，如实施例1至3所示的那样。
有益效果
1.本发明的组合是新型组合，该组合具有降低的副作用和提高的功效。
2.本发明的组合稳定且具有协同效果。
以下实施例进一步详细示出了本发明及其独特的特征。然而以下实施例绝不旨在限制本发明的范围。
实施例1：表儿茶素与PI3K/mTOR抑制剂(化合物1004)的组合的协同效果的评价
对于免疫缺陷的小鼠的癌症异种移植模型，评价表儿茶素与PI3K/mTOR抑制剂的组合的抗癌潜能。给予CD-1裸鼠载体对照、PI3K/mTOR抑制剂、以及PI3K/mTOR抑制剂和表儿茶素的组合，给药周期为21天。发现在(G-3)组中肿瘤体积的减小量最大，即当组合给药时，肿瘤生长抑制％(TGI％)为97％。结果示出于表2、表3和图1a、图1b中。
表2：表儿茶素和化合物No.1004的组合在小鼠的HCT116诱导异种移植模型中的结果
TG：肿瘤生长抑制
T/C：第21天的治疗/对照
表3：表儿茶素和化合物No.1004的组合在减小肿瘤重量方面的结果
从表2和表3以及图1a和图1b所展示的数据可看出，表儿茶素和化合物1004的组合可协同作用。
实施例2：(-)表儿茶素和顺铂的组合的协同效果的评价
2.1细胞培养：使用Hell-299细胞系(对应于正常肺细胞)作为正常细胞对照，并且在5％CO2、37℃的标准条件下培养A549细胞系(对应于肺腺癌)。用不同浓度的顺铂[CDDP(顺-二胺二氯铂(II)，Sigma)][1μM-100μM]、或(-)表儿茶素(EC，Sigma)[0.1μM至1000μM]、或这两种化合物的组合对细胞进行处理48小时。这两种化合物均溶解于DMSO中(0.9％)。
2.2细胞存活率：通过MTT分析确定细胞存活率。简而言之，在37℃下，用0.1mg/ml的MTT(3-(4,5-二甲基-2-噻唑基)-2,5-二苯基四唑溴化物)培育细胞40分钟。使用0.01M的HCl-异丙醇溶解紫色甲臜。用分光光度法在595nm下测定溶解物(BioteckSynergy HT)。
细胞存活率计算如下：
细胞存活率：
等效线图解分析：在确定EC和CDDP的浓度响应曲线之后，进行等效线图解分析。该方法首先能够理论分析剂量组合的效果，其基于Tallarida报道的工作(其对任意两种药物之间的相互作用的类型进行了定量评价并以图形示出)。简而言之，在计算各化合物的抑制浓度(IC)之后，根据方程式(Eq.(1))获得比率固定为1:1的组合的理论值(例如，IC50、IC30和IC15)，然后代入试验值(Eq.(2))。
方程式(1)
这表示，为了确定是否存在累加效应，1/2EC有效浓度+1/2CDDP有效浓度必须为1(一)。例如，在以下组合1/2EC(IC30)+1/2CDDP(IC30)中，如果存在累加效应，则在实验条件下存在30％的抑制作用。
然后通过同时施用1/2EC(ICx)+1/2CDDP(ICx)浓度，从而实验性地评价EC与CDDP的相互作用，其中ICx对应于不同浓度，但是全部为1:1的比率。采用由这些组合所获得的实验结果，并对这两种化合物之间观察到的相互作用的类型进行确定：
方程式(2)
如上所述，当实验得到的结果等于1时，存在累加效应。如果结果＜1，则存在协同效应或超累加(supradditive)效应，而如果结果＞1，则结果是对抗的。
细胞凋亡分析(吖啶橙/溴化乙锭染色)
利用吖啶橙/溴化乙锭染色[15mM/0.002mM]评价细胞凋亡的存在。吖啶橙(AO)将细胞核染色为绿色。仅当质膜完整性受损时，溴化乙锭(EB)才将细胞核染色为红色。使用落射荧光显微镜(Nikon Elipse E600)采集图像。状态良好的活细胞呈现有光泽的绿色染色。凋亡过程中的细胞和死细胞显示出有光泽的红色染色。
使用ImageJsoftware(1.38x版本，http://rsb.info.nih.gov/ij)评价绿色和红色荧光强度
在A549细胞系中评价表儿茶素和顺铂在降低细胞毒性中的协同活性。图2a示出了A549细胞中顺铂的细胞毒性作用，图2b示出了A549细胞中表儿茶素的细胞毒性作用。通过等效线图解示出了本发明的组合的效果。图2c示出了等效线图解的构建和解释以供参考。图2d示出了本发明的组合的等效线图解。位于相加线下方的红点表示获得30％的作用(细胞毒性)所需的两种化合物的实验组合。当将(-)表儿茶素和顺铂组合时，实现30％的细胞生长抑制所需的(-)表儿茶素和顺铂的浓度远低于单独使用这两种化合物时实现相同效果所需的剂量。进行了数理分析以确定联合作用指数(γ)。
γ＝1 累加
γ＜1 协同
γ＞1 对抗
结果：由图3可看出，根据本发明的(-)表儿茶素和顺铂的组合在基于肺癌细胞系(如NCI-HI299和HCC-827)的细胞毒性模型中具有协同效应。
从图4中可看出，与单独测试(-)表儿茶素和顺铂时的细胞凋亡作用相比，(-)表儿茶素和顺氯氨铂的组合在诱导癌细胞系的细胞凋亡中具有协同效应。

Claims (13)

1.一种表儿茶素与至少一种抗癌化合物的新型组合。
2.根据权利要求1所述的组合，其中所述表儿茶素选自由(+)表儿茶素、(-)表儿茶素、或者(+)表儿茶素和(-)表儿茶素的混合物组成的组。
3.根据权利要求1所述的组合，其中(+)表儿茶素:(-)表儿茶素的比例在0.1:99.9至99.9:0.1的范围内。
4.根据权利要求1所述的组合，其中所述表儿茶素:所述抗癌化合物的比例在0.1:99.9至99.9:0.1的范围内。
5.根据权利要求1所述的组合，其中所述抗癌化合物选自由下列组成的组：烷基化抗肿瘤化合物，如环磷酰胺、亚硝基脲、醇磺酸盐；铂配位化合物，如顺铂、卡铂、奥沙利铂；抗代谢物，如氨甲喋呤、6-巯基嘌呤和5-氟尿嘧啶(5-FU)、吉西他滨；抗肿瘤抗生素，如阿霉素；微管抑制剂，如多西他赛、紫杉醇、拓扑替康、依托泊苷、依立替康、长春碱；生物化合物，如伊马替尼、拉帕替尼、舒尼替尼、索拉非尼、坦罗莫司；双膦酸盐，如伊班膦酸、唑来膦酸免疫治疗化合物；靶向抗癌治疗化合物和其他一般的化疗化合物，如由下列组成的组：选择性或非选择性的PI3激酶抑制剂、mTOR抑制剂、MEK抑制剂、Akt抑制剂、酪氨酸激酶抑制剂，如针对EGF受体的伊马替尼、埃罗替尼和吉非替尼；FGF、VEGF、PDGF的舒尼替尼抑制剂；ALK抑制剂、ABL、SCR、FLT3、KIT、MET抑制剂、BRAF抑制剂、Ilβ抑制剂、JAK1/2、JAK3抑制剂、蛋白体抑制剂硼替佐米、其他生长因子抑制剂、RAS/RAF/MAPK途径抑制剂和其他信号转导抑制剂、多靶点激酶抑制剂、拓扑异构酶抑制剂、糖酵解抑制剂、组织蛋白酶B抑制剂、组蛋白脱乙酰基酶抑制剂等，其可单独使用或者与其他抗癌化合物组合使用，优选地，所述抗癌化合物选自由下列组成的组：含铂抗癌药物如顺铂、卡铂或奥沙利铂，化疗化合物如PI3激酶/mTOR抑制剂。
6.根据权利要求1和权利要求5所述的组合，其中具有PI3激酶/mTOR的所述抗癌化合物选自由下列组成的组：
i.4-(4-(2-氨基噻唑-5-基)-6-吗啉代-1,3,5-三嗪-2-基氧基)-N,N-二甲基苯甲酰胺；
ii.4-(4-(2-氨基噻唑-5-基)-6-吗啉代-1,3,5-三嗪-2-基氧基)-N,N-二甲基苯甲酰胺；
iii.(S)-4-((4-(2-氨基噻唑-5-基)-6-(3-甲基吗啉代)-1,3,5-三嗪-2-基)氧基)-3-氟-N,N-二甲基苯甲酰胺；
iv.(S)-4-((4-(6-氨基吡啶-3-基)-6-(3-甲基吗啉代)-1,3,5-三嗪-2-基)氧基)-3-氟-N,N-二甲基苯甲酰胺。
7.根据权利要求1和权利要求5所述的组合，其中具有PI3激酶/mTOR的所述抗癌化合物选自由下列组成的组：
8.一种新型组合物，其包含根据权利要求1所述的组合以及其他可药用的赋形剂。
9.根据权利要求1所述的新型组合在癌症治疗中实现协同效应的用途。
10.根据权利要求1所述的新型组合在降低患者对抗癌组合产生耐药性的风险方面的用途。
11.根据权利要求1所述的新型组合在降低与肥胖相关的作用方面的用途。
12.根据权利要求1所述的新型组合在诱导对癌细胞的免疫应答方面的用途。
13.根据权利要求1所述的新型组合在降低瓦伯格效应方面的用途。
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