CN116350789A - 一种基于抑制phgdh活性的组合物的抗肿瘤用途 - Google Patents
一种基于抑制phgdh活性的组合物的抗肿瘤用途 Download PDFInfo
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Abstract
本发明属于医药技术领域，公开了一种基于抑制PHGDH活性的抗肿瘤药物组合物。本发明所公开的抗肿瘤药物组合物，对肺癌等多种肿瘤具有显著的治疗作用，具有良好临床应用前景。
Description
技术领域
本发明涉及一种基于抑制PHGDH活性的抗肿瘤药物组合物及其用途，具体涉及包含PHGDH抑制剂和化疗药物的组合物及其抗肿瘤用途，属于医药技术领域。
背景技术
靶向肿瘤依赖性氨基酸代谢是近年来抗肿瘤药物研发的热门领域。丝氨酸是继葡萄糖和谷氨酸外第三大肿瘤细胞代谢相关物质，与肿瘤的发生和发展密切相关。肺癌、乳腺癌、结肠癌等多种肿瘤也存在丝氨酸合成途径异常活化的现象。磷酸甘油酸脱氢酶(Phosphoglycerate dehydrogenase,PHGDH)是丝氨酸合成途径中关键的分支酶，并高表达于肿瘤组织中。研究证据表明，肿瘤细胞内高表达的PHGDH可促进内源性丝氨酸从头合成，为肿瘤快速增殖的肿瘤细胞提供生物大分子；不仅如此，PHGDH还能将a-酮戊二酸(a-KG)还原成致癌代谢物D-2-羟基戊二酸(D-2-HG)，促进肿瘤恶性转化。敲低PHGDH基因和给予PHGDH抑制剂均可显著抑制肿瘤生长，PHGDH也成为肿瘤治疗和药物发现的新靶点。
目前针对PHGDH靶点开发了一系列抑制剂，但因为选择性差或有效性欠佳等原因，均未进入临床试验。筛选合适的目标人群，并建立有效的PHGDH抑制剂联用化疗药物组合方案不仅能显著提高临床治疗效果，甚至可以逆转耐药性的产生。
发明内容
本发明的目的为解决上述现有技术的缺点与不足，针对特定肿瘤患者群体，提供一种基于抑制PHGDH活性的组合物的抗肿瘤用途。
本发明所采用的技术方案如下：
一种组合物，其特征在于，所述组合物包含抑制PHGDH抑制剂和化疗药物。较佳地，所述PHGDH抑制剂，包含抑制PHGDH活性或表达的小分子化合物、siRNA、或PROTAC分子等；所述抑制PHGDH的小分子化合物为NCT-503、CBR-5884、双硫仑或果酸内酯A。优选地，所述PHGDH小分子抑制剂为NCT-503，CBR-5884。所述化疗药物为本领域常规的化疗药物，如顺铂、卡铂、培美曲塞、紫杉醇或5-氟尿嘧啶。
本发明还包括所述治疗和/或预防肿瘤的药物是基于抑制PHGDH活性的抗肿瘤药物。所述应用中的肿瘤为本领域常规的肿瘤，较佳地，是肺癌、脑胶质瘤、肠癌、胰腺癌、乳腺癌以及肝癌。
所述预防是本领域常规的预防，较佳地指存在可能的肿瘤因素时，使用后防止或降低肿瘤的产生。所述治疗是本领域常规的治疗，较佳地指减轻肿瘤的程度，或者治愈肿瘤使之正常化，或者减缓肿瘤的进程。
本发明的有益技术效果在于：
1、本发明所述基于抑制PHGDH活性的抗肿瘤药物组合物，在提高肿瘤患者化疗治疗效果，以及在制定临床抗肿瘤治疗策略上有广泛的应用。
2、本发明筛选出所述基于抑制PHGDH活性的抗肿瘤药物组合物合适的目标患者人群，即肺癌、脑胶质瘤、肠癌、胰腺癌、乳腺癌以及肝癌等实体瘤肿瘤患者。优选地，是IDH1高表达的肺癌患者。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实验例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实验例中所述的生理盐水，指浓度为0.9％的氯化钠溶液。
实验例中所述药物，给药剂量和时间如下：NCT-503(40mg/kg，一天一次)、CBR-5884(50mg/kg，一天一次)、双硫仑(30mg/kg，一天一次)、果酸内酯A(100mg/kg，一天一次)、顺铂(3mg/kg，一周一次)、卡铂(30mg/kg，一周一次)、培美曲塞(100mg/kg，一天一次)、紫杉醇(20mg/kg，一周一次)或5-氟尿嘧啶(5mg/kg，一天一次)。
实验例中所述的室温为本领域常规的室温，较佳地为15～30℃。
实验结果用均值±标准误表示，经参数或者非参数方差检验，经比较p<0.05认为有显著性差异，p<0.01认为有极其显著性差异。
实验例1:GSEA法证明IDH1高表达患者丝氨酸合成通路活化
从UCSC Xena平台(https://xena.ucsc.edu/)获取癌症基因组图谱TCGA数据库肺腺癌相关数据LUAD HiSeqV2_PANCAN(n＝576)。按照IDH1表达高低将肺癌患者分为IDH1高表达组(90％～100％,n＝58)和IDH1低表达组(0％～10％,n＝58)。获取GSEA平台Serineand Glycine One Carbon和Serine Family Amino Acid Metabolic Process数据集(http://www.gsea-msigdb.org/gsea/index.jsp),使用GSEA v4.1.0软件进行信号通路分析,FDR q(false discovery rate q value)<0.25视为具有显著性差异。GSEA分析结果显示，IDH1高表达的患者中丝氨酸甘氨酸一碳代谢通路基因富集(图1)。
实验例2:Western blotting法证明IDH1能够促进肿瘤细胞PHGDH等关键丝氨酸代谢酶的蛋白表达
蛋白提取裂解液：RIPA裂解液中加入蛋白酶抑制剂(protein inhibitorcocktail,PIC)和PMSF。具体操作步骤如下：
利用慢病毒构建稳定敲低IDH1的PC9细胞株(PC9/IDH1-shRNA)及其对照细胞(PC9/Control-shRNA)。收取生长状况良好且处于对数生长期的PC9/IDH1-shRNA细胞及PC9/Control-shRNA细胞，用预冷的PBS清洗两遍后转移至1.5ml离心管中，加入200μl上述蛋白提取裂解液。冰上裂解30min,4℃12000rpm离心30min。吸取上清，使用BCA法对蛋白进行定量并将蛋白调整至相同浓度。加入5×SDS凝胶加样缓冲液，混匀后98℃变性10min。取部分蛋白样品进行SDS-聚丙烯酰胺凝胶电泳。Western blotting结果显示，与对照细胞相比，PC9/IDH1-shRNA细胞中PHGDH蛋白水平下调最明显(图2)。
实验例3:通过人肺腺癌PC9皮下成瘤实验研究PHGDH抑制剂联用化疗药物组合物对肿瘤生长的影响
实验1:
小鼠实验分为4大组：对照溶剂处理组(生理盐水)、PHGDH抑制剂单独处理组(NCT503、CBR-5884、Disulfiram、Indole derivative 3)、化疗药物单独处理组(顺铂、卡铂、培美曲塞、5-氟尿嘧啶、吉西他滨)及PHGDH抑制剂和化疗药物联合处理组(NCT503+顺铂、NCT503+卡铂、NCT503+培美曲塞、NCT503+5-氟尿嘧啶、NCT503+吉西他滨、CBR-5884+顺铂、CBR-5884+卡铂、CBR-5884+培美曲塞、CBR-5884+5-氟尿嘧啶、CBR-58843+吉西他滨、Disulfiram+顺铂、Disulfiram+卡铂、Disulfiram+培美曲塞、Disulfiram+5-氟尿嘧啶、Disulfiram+吉西他滨、Indole derivative 3+顺铂、Indole derivative 3+卡铂、Indolederivative 3+培美曲塞、Indole derivative 3+5-氟尿嘧啶、Indole derivative 3+吉西他滨)
上述成瘤实验所采用的小鼠品系为BALB/C-Nude，所采用的肿瘤细胞株为人肺腺癌细胞株PC9。在皮下种植PC9细胞一周后进行PHGDH抑制剂或化疗药物的腹腔注射给药。
结果表明，PHGDH抑制剂/化疗药物联合给药较单独给药能更好的抑制肿瘤生长，其中NCT503/吉西他滨具有最好的抑制肿瘤生长的作用(表1)。
表1.PHGDH抑制剂联用化疗药物组合物抑制肺癌细胞PC9的生长
实验2:
小鼠实验分为4大组：PC9/Control-shRNA+溶剂对照组、PC9/PHGDH-shRNA+溶剂对照组、PC9/Control-shRNA+化疗药物处理组(顺铂、卡铂、培美曲塞、5-氟尿嘧啶、吉西他滨)及PC9/PHGDH-shRNA+化疗药物联合处理组(顺铂、卡铂、培美曲塞、5-氟尿嘧啶、吉西他滨)。
上述成瘤实验所采用的小鼠品系为BALB/C-Nude，所采用的肿瘤细胞株为人肺腺癌细胞株PC9/Control-shRNA或PC9/PHGDH-shRNA。在皮下种植细胞一周后进行化疗药物的腹腔注射给药。
结果表明，敲低PHGDH可增强化疗药物敏感性，其中对吉西他滨的增敏效果更加明显(表2)。
表2.敲低PHGDH增加化疗药物敏感性
实验3:
小鼠实验分为2组：根据接种细胞类型分为PC9/Control-shRNA组及PC9/IDH1-shRNA组，两组均给予PHGDH抑制剂和化疗药物联合处理。
上述成瘤实验所采用的小鼠品系为BALB/C-Nude，所采用的肿瘤细胞株为人肺腺癌细胞株PC9/Control-shRNA组及PC9/IDH1-shRNA组。皮下种植PC9/Control-shRNA组及PC9/IDH1-shRNA细胞，待肿瘤大小长至100mm3时，进行PHGDH抑制剂或化疗药物的腹腔注射给药。
结果表明，与对照组相比，PC9/IDH1-shRNA组对于PHGDH抑制剂/化疗药物联合处理不敏感(表3)。
表3.肺癌细胞PC9/IDH1-shRNA对PHGDH抑制剂联用化疗药物组合物不敏感
实验例4:通过皮下成瘤实验研究PHGDH抑制剂联用化疗药物组合物对生长的脑胶质瘤、肠癌、胰腺癌、乳腺癌以及肝癌影响
首先培养可以稳定传代的肺癌细胞系PC9、脑胶质瘤细胞系U251、肠癌细胞系HCT116、胰腺癌细胞系PANC-1、乳腺癌细胞系MDA-MB-231以及肝癌细胞系Hep3B。
上述小鼠实验每个癌种分为2组：对照溶剂处理组以及PHGDH抑制剂和化疗药物联合处理组。
上述成瘤实验所采用的小鼠品系为BALB/C-Nude，所采用的肿瘤细胞株分别为人肺腺癌细胞株PC9、人脑胶质瘤细胞系U251、人肠癌细胞系HCT116、人胰腺癌细胞系PANC-1、人乳腺癌细胞系MDA-MB-231以及人肝癌细胞系Hep3B。在皮下种植相同数量的上述细胞一周后，随机分为2组，分别给予对照溶剂或PHGDH抑制剂和化疗药物联合给药，25天后根据肿瘤体积分别计算肿瘤抑制率。(计算方法为：肿瘤抑制率＝(1-联合给药组瘤体积/对照组瘤体积)*100％
结果表明，肺癌对于PHGDH抑制剂联用化疗药物的组合物具有更高的肿瘤抑制率(表4)。
表4.PHGDH抑制剂联用化疗药物组合物对不同癌种的肿瘤抑制率
Claims (7)
1.一种组合物，其特征在于，所述组合物包含PHGDH抑制剂和化疗药物。
2.根据权利要求1所述的组合物，其特征在于，所述PHGDH抑制剂选自小分子化合物、siRNA、或PROTAC分子。
3.根据权利要求2所述的组合物，其特征在于，小分子化合物选自NCT503、CBR-5884、双硫仑或果酸内酯A；优选地，所述PHGDH小分子抑制剂为NCT-503，CBR-5884。
4.根据权利要求1所述的组合物，其特征在于，所述化疗药物选自顺铂、卡铂、培美曲塞、吉西他滨、紫杉醇、5-氟尿嘧啶。
5.权利要求1所述的组合物在制备治疗和/或预防肿瘤的药物中的应用。
6.根据权利要求5的应用，其特征在于，所述治疗和/或预防肿瘤的药物是基于抑制PHGDH活性的抗肿瘤药物。
7.根据权利要求5的应用，其特征在于，所述肿瘤选自肺癌、脑胶质瘤、肠癌、胰腺癌、乳腺癌或肝癌。
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