CN115364231B - 一种增强ezh2抑制剂抗肿瘤作用的药物组合物及其用途 - Google Patents
一种增强ezh2抑制剂抗肿瘤作用的药物组合物及其用途 Download PDFInfo
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Abstract
本发明属于医药领域，提供了一种增强EZH2抑制剂抗肿瘤作用的药物组合物，所述药物组合物包含EZH2抑制剂和PPARα激动剂，其中所述PPARα激动剂增强所述EZH2抑制剂抗实体瘤的作用。本发明还提供了所述药物组合物的相关制剂及其在制备抗肿瘤药物中的用途。实验结果表明，将EZH2抑制剂GSK126与PPARα激动剂非诺贝特联合用于治疗B16F10、SMMC7721和GL261细胞，发现与非诺贝特的联用确实可以显著增强GSK126对细胞增殖的抑制作用。本发明为临床上能够安全、有效、方便、经济地使用EZH2抑制剂治疗实体瘤提供一种新思路，临床应用前景良好，且为非诺贝特的老药新用提供证据。
Description
本发明要求2021年10月15日提交的中国专利申请CN202111201508.4的优先权，该优先权文件的说明书、说明书附图和权利要求书所记载的内容全文引入本发明的说明书并被作为本发明说明书原始记载的一部分。申请人进一步声明，申请人拥有基于该优先权文件修改本发明的说明书和权利要求书的权利
技术领域
本发明属于医药领域，具体涉及一种增强EZH2抑制剂抗肿瘤作用的药物组合物及其在制备抗肿瘤药物中的用途。
背景技术
Zeste基因增强子同源物2(Enhancer of zeste homolog 2，EZH2)是多梳抑制复合物2(polycomb repressive complex 2，PRC2)的催化亚基，发挥组蛋白甲基转移酶的作用。许多疾病(如肿瘤)中都存在EZH2的异常，多个证据表明EZH2与多种癌症的发生和进展以及预后不良有关。EZH2过表达主要见于实体瘤，包括***癌、乳腺癌、膀胱癌、子宫内膜癌和黑色素瘤等，高水平的EZH2表达常常与这些类型肿瘤的高侵袭性、肿瘤进展期、具有较差的临床结果和预后相关联。
与正常细胞不同，肿瘤细胞通过致癌突变直接或间接调节细胞代谢重编程，以满足它们的生存和增殖需求。表观遗传机制可以调节参与代谢基因的表达，从而改变细胞的代谢特征。EZH2作为组蛋白修饰的关键调节因子，参与调节肿瘤细胞的多种代谢活动，从而影响肿瘤的进程。
EZH2在肿瘤细胞也能促进脂质合成。在含有端粒酶逆转录酶(telomerasereverse transcriptase，TERT)突变神经胶质瘤细胞中，TERT和EZH2水平成正相关，TERT-EZH2相互协同激活过氧化物酶体增殖物激活受体γ共激活因子1-α(Peroxisomeproliferator-activated receptor gamma coactivator 1-α，PGC-1α)，而脂肪酸合成酶(FASN)的表达依赖于PGC-1α，从而EZH2通过TERT-EZH2网络促进了脂肪酸合成和蓄积。并且有研究称肿瘤细胞中高水平脂肪酸可以通过负调节DNA损伤修复(DDR)途径促进肿瘤发生和耐药性。但相反的是，EZH2抑制剂DZNep会诱导在非酒精性脂肪肝细胞和某些癌细胞系(如乳腺癌)中的脂质积累。为了阐明这种差异，有学者利用原代人类、小鼠前脂肪细胞和特异性敲除脂肪细胞中EZH2的小鼠，研究了EZH2在脂肪细胞分化和脂质代谢中的作用。他们发现抑制EZH2或基因缺失促进了载脂蛋白E(Apolipoprotein E，ApoE)基因表达上调，并伴随着脂蛋白依赖性脂质的吸收，最终导致胞质内脂质蓄积。但不影响脂肪细胞标志物基因的表达和脂肪细胞分化。这与以往研究中发现EZH2促进小鼠脂肪祖细胞脂肪形成分化的结论是相悖的。因此，EZH2在肿瘤细胞中对脂代谢的调节作用还不是很清楚，EZH2是如何影响到脂肪酸、甘油三酯、酮体等脂代谢产物的，以及这些代谢产物在肿瘤进程中又扮演着怎么样的角色，还需要进一步的探讨。
通过高通量筛选已经获得了许多高效和具有选择性的EZH2催化抑制剂，如EPZ005687、EI1、GSK343、GSK126等，其结构中几乎全部都带有2-吡啶酮基团。目前已开发了许多EZH2抑制剂作为潜在的抗癌药物。其中，CPI1205(Lirametostat)已通过临床试验测试，EPZ-6438(Tazemetostat)于2020年被FDA批准用于治疗上皮样肉瘤。但是，在EZH2过表达的实体瘤中，EZH2抑制剂效果不佳，如胶质瘤和黑素瘤中Ras通路和SWI/SNF的同时突变能够逃逸EZH2抑制剂的抗肿瘤效应。因此，研究人员试图尝试通过采用联合多种药物或多种抗肿瘤治疗手段的治疗策略改善EZH2抑制剂的疗效(参见，例如，Zhang Tengrui,etal.,Symphony of epigenetic and metabolic regulation-interaction between thehistone methyltransferase EZH2 and metabolism of tumor,Clinical Epigenetics,2020,12:72)。
此外，本发明人此前的研究成果显示，由EZH2介导的表观遗传调控和代谢改变显示了在癌细胞中的协同作用。本发明人初步发现EZH2抑制剂治疗效果不佳可能是由于脂质代谢失调导致的。并且，在多项研究中已发现几种典型的降脂药物具有抗癌作用，尤其是贝特类药物和他汀类药物。非诺贝特(FF)对乳腺癌、口腔肿瘤、黑色素瘤、肺癌、胶质母细胞瘤和肝癌等具有抗癌活性。相关作用涉及促进细胞凋亡，阻滞细胞周期，抑制侵袭和迁移等。
鉴于以上的研究背景，本发明人推测联合脂代谢药物可能在针对某些抗肿瘤药物的联合疗法中具有重要作用，这很可能为解决EZH2抑制剂治疗效果不佳提供了一种新思路。
发明内容
本发明的目的在于针对EZH2抑制剂对于实体瘤的活性不佳的问题，提供了一种能够增强EZH2抑制剂抗肿瘤作用的包含EZH2抑制剂和PPARα激动剂的药物组合物，为临床上能够安全、有效、方便、经济地使用EZH2抑制剂治疗实体瘤提供一种新思路。
具体地，通过以下几个方面的技术方案实现了本发明：
在第一个方面中，本发明提供了一种增强EZH2抑制剂抗肿瘤作用的药物组合物，所述药物组合物包含EZH2抑制剂和PPARα激动剂，其中所述PPARα激动剂增强所述EZH2抑制剂抗实体瘤的作用。
作为可选方式，在上述药物组合物中，所述EZH2抑制剂与所述PPARα激动剂的质量比为1：1-1：10，实质上，所述EZH2抑制剂与所述PPARα激动剂在药物组合物中的用量比例可以由临床医师根据患者所患癌症的种类根据临床经验确定。
优选地，所述EZH2抑制剂与所述PPARα激动剂的质量比选自1：1、1：2、1：3、1：4、1：5、1：6、1：7、1：8、1：9或1：10。
作为可选方式，在上述药物组合物中，所述实体瘤选自：乳腺癌、***癌、黑色素瘤、骨肉瘤、神经母细胞瘤、胰腺癌、肺癌、横纹肌肉瘤、尤因肉瘤、膀胱癌、结肠癌、肝癌、卵巢癌、***、鼻咽癌、喉癌、胃癌、肾癌、头颈部肿瘤、食管癌、睾丸癌、甲状腺癌或脑癌。
优选地，所述实体瘤选自：乳腺癌、黑色素瘤、肺癌、结肠癌、肝癌、胃癌或脑癌。
更优选地，所述脑癌选自：脑膜瘤、神经胶质瘤(例如，星形细胞瘤、少突胶质瘤)或髓母细胞瘤。
作为可选方式，在上述药物组合物中，所述EZH2抑制剂选自：Tazemetostat(EPZ-6438)、GSK126、Lirametostat(CPI-1205)、SHR2554或PF-06821497；所述PPARα激动剂选自：非诺贝特、氯贝特、苯扎贝特、克利贝特、环丙贝特、依托贝特、吉非罗齐、WY-14643(匹立尼酸)、GW-7647(2-(4-(2-(1-1-环己烷丁基)-3-环己基酰脲)乙基)苯基硫基)-2-甲基丙酸)或佩玛贝特((R)-2-{3-{[N-(苯并噁唑-2-基)-N-3-(4-甲氧基苯氧基)丙基]氨基甲基}苯氧基}丁酸)。
作为可选方式，在上述药物组合物中，优选地，所述EZH2抑制剂为GSK126，所述PPARα激动剂为非诺贝特。
在第二个方面中，本发明提供了一种增强EZH2抑制剂抗肿瘤作用的药物制剂，所述药物制剂由治疗有效量的上述第一个方面所述的药物组合物和药学上可接受的载体制成。
作为可选方式，在上述药物制剂中，所述药物制剂为口服制剂。
优选地，所述口服制剂是口服液、片剂、粉剂、胶囊剂或颗粒剂。
在第三个方面中，本发明提供了上述第一个方面所述的药物组合物或者上述第二个方面所述的药物制剂在制备抗肿瘤药物中的用途。
作为可选方式，在上述用途中，所述肿瘤是实体瘤。
所述实体瘤选自：乳腺癌、***癌、黑色素瘤、骨肉瘤、神经母细胞瘤、胰腺癌、肺癌、横纹肌肉瘤、尤因肉瘤、膀胱癌、结肠癌、肝癌、卵巢癌、***、鼻咽癌、喉癌、胃癌、肾癌、头颈部肿瘤、食管癌、睾丸癌、甲状腺癌或脑癌，优选地，所述实体瘤选自：乳腺癌、黑色素瘤、肺癌、结肠癌、肝癌、胃癌或脑癌。
更优选地，所述脑癌选自：脑膜瘤、神经胶质瘤(例如，星形细胞瘤、少突胶质瘤)或髓母细胞瘤。
在第四个方面中，本发明提供了PPARα激动剂在制备增强EZH2抑制剂抗实体瘤疗效的药物中的用途。
所述实体瘤选自：乳腺癌、***癌、黑色素瘤、骨肉瘤、神经母细胞瘤、胰腺癌、肺癌、横纹肌肉瘤、尤因肉瘤、膀胱癌、结肠癌、肝癌、卵巢癌、***、鼻咽癌、喉癌、胃癌、肾癌、头颈部肿瘤、食管癌、睾丸癌、甲状腺癌或脑癌。
优选地，所述实体瘤选自：乳腺癌、黑色素瘤、肺癌、结肠癌、肝癌、胃癌或脑癌。
更优选地，所述脑癌选自：脑膜瘤、神经胶质瘤(例如，星形细胞瘤、少突胶质瘤)或髓母细胞瘤。
所述EZH2抑制剂选自：Tazemetostat(EPZ-6438)、GSK126、Lirametostat(CPI-1205)、SHR2554或PF-06821497。
所述PPARα激动剂选自：非诺贝特、氯贝特、苯扎贝特、克利贝特、环丙贝特、依托贝特、吉非罗齐、WY-14643(匹立尼酸)、GW-7647(2-(4-(2-(1-1-环己烷丁基)-3-环己基酰脲)乙基)苯基硫基)-2-甲基丙酸)或佩玛贝特((R)-2-{3-{[N-(苯并噁唑-2-基)-N-3-(4-甲氧基苯氧基)丙基]氨基甲基}苯氧基}丁酸)。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一赘述。
本发明相对于现有技术，具有以下有益效果：
本发明人首次发现通过将EZH2抑制剂与PPARα激动剂联合使用，能够显著增强EZH2抑制剂治疗实体瘤的疗效，并在此基础上提供了一种能够增强EZH2抑制剂抗肿瘤作用的包含EZH2抑制剂和PPARα激动剂的药物组合物，为临床上能够安全、有效、方便、经济地使用EZH2抑制剂治疗实体瘤提供一种新思路，临床应用前景良好。
附图说明
图1：血液***肿瘤比实体瘤对GSK126更敏感。(A)通过Incucyte S3监测GSK126(10-20μM)处理中B16F10，Huh7和SMMC7721细胞的增殖情况，每组设置6次重复；(B)通过CCK-8测定法测量GSK126(200nM-24μM)处理24h和48h后Daudi和THP-1细胞的活力，每组设置5次重复；(C)在无或有GSK126处理(6μM，12μM)48h后对B16F10细胞的蛋白质印迹分析(WB)，H3用作组蛋白内参。每组设置5-6次重复，*P<0.05，**P<0.01，***P<0.001，ns表示无统计学差异。
图2：黑色素瘤细胞B16F10对GSK126的敏感性较低。(A)细胞划痕实验显示了GSK126(10μM)治疗对B16F10细胞迁移能力的影响，每组设置3次重复；(B-C)通过流式细胞术(C)和膜联蛋白V染色(Annexin V)测定法检测GSK126(10、13、15μM)对B16F10细胞凋亡率的影响。每组设置3次重复，*P<0.05，**P<0.01，***P<0.001，ns表示无统计学差异。
图3：GSK126导致黑色素瘤B16F10细胞中6种脂肪酸显著升高。
图4：GSK126治疗后的小鼠出现脂质蓄积。(A)对照组和GSK126治疗组的荷瘤小鼠肝脏组织切片H&E和油红O染色，右图为阴性或阳性染色面积的统计结果(每组3次重复)；(B)对照组和GSK126治疗组的荷瘤小鼠血清中TG水平(每组5次重复)；(C-D)通过RT-qPCR和WB检测GSK126处理的HCC细胞中脂肪酸合成代谢相关基因的mRNA(C)和蛋白质(D)水平(每组3次重复)。每组3-5次重复，*P＜0.05，**P<0.01。
图5：脂代谢调节药物能够抑制肿瘤细胞的增殖。(A)根据ONCOMINE数据库分析，肝癌(GSE14520)和黑素瘤(GSE3189)患者组织中ACLY和FASN的mRNA水平上调；(B)TCGA LIHC(肝癌)和GSE8401(黑素瘤)数据集中患者的Kaplan-Meier生存曲线。具有ACLY高表达的HCC患者和FASN高表达的黑色素瘤患者的总生存期明显降低。P＝0.0108，P＝0.0385，Kaplan-Meier生存分析；(C)不同浓度的替米沙坦对U87细胞(左)和U251细胞(右)增殖的影响(每组3次重复)；(D)不同浓度的非诺贝特对B16F10细胞(左)和4T1细胞(右)增殖的影响(每组3次重复)；(E)在替米沙坦处理U87和U251细胞48h后，对EdU(FITC+)染色阳性的细胞百分比进行FACS定量分析。首先对单细胞进行门控，然后对FITC+细胞进行门控。FITC+细胞的百分比在相应细胞群上方列出。每组设置3次重复，*P<0.05，**P<0.01，***P<0.001，****P<0.0001，ns表示无统计学差异。
图6：脂质调节药物可以增强GSK126对癌细胞的抑制作用。(A)利用Incucyte S3按对照、非诺贝特治疗(25μM，FF50)、GSK126治疗(10μM，G10)和联合治疗(非诺贝特25μM和GSK126 10μM，GSK126+FF)四个分组监测B16F10和SMMC7712的细胞增殖情况(每组5次重复)；(B)对按(A)中条件进行处理的B16F10细胞和SMMC7712细胞中脂肪酸合成相关基因的mRNA水平进行qRT-PCR测定(每组3次重复)。每组设置3-5次重复，*P<0.05，**P<0.01，***P<0.001。
图7：脂质调节药物可以增强GSK126对脑癌细胞的抑制作用。利用Incucyte S3按对照、非诺贝特治疗(10μM)、GSK126治疗(20μM，40μM)和联合治疗(非诺贝特10μM和GSK12620μM，GSK126+FF)四个分组监测GL261细胞增殖情况。每组设置3-6次重复，*P<0.05，**P<0.01，***P<0.001，ns表示无统计学差异。
具体实施方式
本发明人在对EZH2在肿瘤细胞中对脂代谢的调节作用机制以及EZH2抑制剂抗肿瘤作用机制的深入研究中，通过大量筛选，首次发现通过将EZH2抑制剂与PPARα激动剂联合使用，能够显著增强EZH2抑制剂治疗实体瘤的疗效。在此基础上完成了本发明。
如本文所用，本发明药物组合物中的EZH2抑制剂和PPARα激动剂可以在同一药物制剂中施用，也可以在不同药物制剂中施用。在不同药物制剂中施用的情况下，EZH2抑制剂和PPARα激动剂的剂型可以是相同的，也可以是不同的。并且，EZH2抑制剂和PPARα激动剂可以同时或顺序施用。
如本文所用，在本发明中，PPARα激动剂是指活化PPARα型受体(其参与作为核内受体之一的过氧化物酶体增殖物应答性受体(PPAR)中的脂肪氧化等)的化合物的总称。具体而言，列举：非诺贝特、氯贝特、苯扎贝特、克利贝特、环丙贝特、依托贝特、吉非罗齐等贝特类；WY-14643(匹立尼酸)；GW-7647(2-(4-(2-(1-1-环己烷丁基)-3-环己基酰脲)乙基)苯基硫基)-2-甲基丙酸)；佩玛贝特((R)-2-{3-{[N-(苯并噁唑-2-基)-N-3-(4-甲氧基苯氧基)丙基]氨基甲基}苯氧基}丁酸)等。
本发明药物组合物治疗的肿瘤的非限制性实例可以包括但不限于：胆道癌(例如，胆管癌)、膀胱癌、乳腺癌(例如，乳腺腺癌、乳腺***状癌、乳腺癌、乳腺髓样癌、三阴乳腺癌、HER2阴性乳腺癌、HER2阳性乳腺癌、男性乳腺癌、晚期转移性乳腺癌、孕激素受体阴性乳腺癌、孕激素受体阳性乳腺癌、复发性乳腺癌)、脑癌(例如，脑膜瘤；神经胶质瘤，例如星形细胞瘤、少突胶质瘤；髓母细胞瘤)、支气管癌、***(例如，***)、绒毛膜癌、结直肠癌(例如，结肠癌、直肠癌、结直肠腺癌)、上皮癌、子宫内膜癌(例如，子宫癌、子宫肉瘤)、食道癌(例如，食道腺癌、巴雷特氏腺癌)、尤因氏肉瘤、眼癌(例如，眼内黑色素瘤、视网膜母细胞瘤)、胆囊癌、胃癌(例如，胃腺癌)、胃肠道间质肿瘤(GIST)、多形胶质母细胞瘤、头颈癌(例如，头颈鳞状细胞癌、口腔癌(例如，口腔鳞状细胞癌(OSCC))、咽喉癌(例如，喉癌、咽癌、鼻咽咽、口咽癌))、肾癌(例如，肾母细胞瘤，又称Wilms肿瘤，肾细胞癌)、肝癌(例如，肝细胞癌(HCC)、恶性肝癌)、肺癌(例如，支气管癌、小细胞癌(SCLC)、非小细胞肺癌(NSCLC)、肺腺癌)、平滑肌肉瘤(LMS)、骨髓增生异常综合征(MDS)、间皮瘤、神经内分泌癌(例如，胃肠胰腺神经内分泌肿瘤(GEP-NET)、类癌肿瘤)、骨肉瘤、卵巢癌(例如，囊腺癌、卵巢胚胎癌、卵巢腺癌)、***状腺癌、胰腺癌(例如，胰腺腺癌、导管内***状粘液性肿瘤(IPMN)、胰岛细胞肿瘤)、***癌(例如，***和阴囊的佩吉特氏病)、***癌(例如，***腺癌)、直肠癌、横纹肌肉瘤、皮肤癌(例如，鳞状细胞癌(SCC)、角膜棘皮瘤(KA)、黑色素瘤、基底细胞癌(BCC))、小肠癌(例如，阑尾癌)、软组织肉瘤(例如，恶性纤维组织细胞瘤(MFH)、脂肪肉瘤、软骨肉瘤、纤维肉瘤)、皮脂腺癌、汗腺癌、滑膜瘤、睾丸癌(例如，***瘤、睾丸胚胎癌)、甲状腺癌(例如，甲状腺***状癌、***状甲状腺癌(PTC)、甲状腺髓样癌)、尿道癌、***癌和外阴癌(例如，外阴佩吉特氏病)。
如本文所用，本发明药物制剂的剂型为片剂、胶囊剂、颗粒剂、口服液或吸入剂。优选地，本发明的剂型为片剂或胶囊剂。
如本文所用，本发明的“药学上可接受的载体”是指药物制剂领域常规的药物载体，选自填充剂、粘合剂、崩解剂、润滑剂、助悬剂、润湿剂、色素、矫味剂、溶剂、表面活性剂中的一种或几种。
本发明所述填充剂包括但不限于淀粉、微晶纤维素、蔗糖、糊精、乳糖、糖粉、葡萄糖等；所述润滑剂包括但不限于硬脂酸镁、硬脂酸、氯化钠、油酸钠、月桂醇硫酸钠、泊洛沙姆等；所述粘合剂包括但不限于水、乙醇、淀粉浆、糖浆、羟丙基甲基纤维素、羧甲基纤维素钠、海藻酸钠、聚乙烯吡咯烷酮等；所述崩解剂包括但不限于淀粉泡腾混合物即碳酸氢钠和枸橼酸、酒石酸、低取代羟丙基纤维素等；所述助悬剂包括但不限于多糖如金合欢胶、琼脂、藻酸、纤维素醚和羧甲基甲壳酯等；所述溶剂包括但不限于水、平衡的盐溶液等。
优选地，可以将本发明的药物制成各种固体口服制剂、液体口服制剂等。药剂学可接受的口服剂固体制剂有：普通片剂、分散片、肠溶片、颗粒剂、胶囊剂、滴丸、散剂等，口服液体制剂有口服液、乳剂等。或者，也可以将本发明的药物制成吸入剂等局部应用剂型。
上述各种剂型可以根据药物制剂领域的常规工艺制备而成。
在上文所述的药物组合物、药物制剂和医药用途中，对于“EZH2抑制剂”和“PPARα激动剂”的给药时间、给药次数和给药频率等等，需要根据病情的具体诊断结果而定，这在本领域技术人员掌握的技术范围之内。例如，将对小鼠或大鼠的治疗方案应用于人体上，所有药物对人的有效剂量可以通过该药物对小鼠或大鼠的有效剂量进行换算，这对于本领域的普通技术人员而言也是容易实现的。
下面参照具体的实施例对本发明做进一步说明。应当理解，此处所描述的具体实施例仅用于解释本发明，并不用于限定本发明的范围。
实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可通过正规渠道购买得到的常规产品。
下面实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为市售产品。
除非另外说明，否则本发明中涉及的百分比和份数均为重量百分比和重量份数。
实施例：
1.多种实体瘤细胞系对EZH2抑制剂GSK126的敏感性较低
为了准确评估实体肿瘤细胞对EZH2抑制剂的反应性，首先利用IncuCyteLive-Cell Analysis System检测了不同浓度的GSK126对黑色素瘤细胞B16F10和肝癌细胞Huh7和SMMC-7721增殖的影响。结果表明，GSK126以剂量依赖性方式抑制细胞增殖，而较高浓度10μM的GSK126的作用效果不佳(图1A)。
在相同的条件下，CCK-8细胞增殖实验结果表明，血液***肿瘤细胞Daudi和THP-1经10μM的GSK126处理24h和48h后增殖却受到明显抑制。特别是Burkitt淋巴瘤细胞Daudi对1μM的GSK126就已经非常敏感(图1B)。与其他研究一致，我们发现实体瘤细胞系通常对EZH2抑制剂不敏感，而许多研究表明，大多数接受GSK126治疗的血液学癌细胞系的IC50(半数最大抑制浓度)低于1μM。
不仅如此，还观察到GSK126在6μM时显著下调了B16F10细胞的H3K27me3水平(图1C)，但在10μM时却不能有效地抑制癌细胞的增殖(图1A)。这表明当GSK126已经能够有效抑制EZH2的组蛋白甲基转移酶活性时，却不能发挥出抗肿瘤效应。
接下来，为了进一步验证10μM的GSK126对黑色素瘤细胞B16F10的效用，进行了划痕实验。与细胞增殖实验相似，培养36h后，与对照组相比，GSK126在10μM时不能有效抑制细胞迁移(图2A)。此外，为了评估GSK126的抗存活作用，用不同浓度的GSK126处理B16F10细胞不同时间，并通过流式细胞术(图2B)和活细胞荧光成像(图2C)分析了细胞的凋亡率。结果表明，10μM的GSK126诱导B16F10细胞凋亡的能力有限。由此可见，较高浓度的GSK126(10μM)处理后，实体瘤细胞B16F10、Huh7和SMMC7721的增殖以及B16F10细胞的迁移和存活没有受到明显抑制。
2.GSK126上调黑色素瘤B16F10肿瘤细胞脂肪酸水平
在发生显著变化的代谢产物中，GSK126处理组中有不少脂肪酸的水平出现上升。其中有五种多不饱和脂肪酸，包括α-亚麻酸，DHA，EPA，亚油酸和γ-亚麻烯酸)和一种单不饱和脂肪酸，包括10Z-庚二烯酸(图3)。
这表明GSK126可以提高脂肪酸丰度。这些脂肪酸可用作脂质合成的底物，以形成质膜结构，但在过度积累时会抑制细胞生长并诱导凋亡。脂肪酸的从头合成能为癌细胞的生物膜结构、能量产生和蛋白质修饰提供原料。而且，肿瘤中高LD和胆固醇酯含量与癌症侵袭能力相关。这提示脂质积累可能是GSK126抗肿瘤疗效不佳的原因。
3.调节脂质代谢可以增强GSK126对癌细胞的抑制作用
3.1GSK126治疗导致小鼠体内脂质蓄积
由于使用GSK126处理的B16F10细胞中多种脂肪酸均上调，因此探讨了荷瘤小鼠脂质代谢的改变。我们选用6-8周龄C57BL/6的小鼠进行皮下荷瘤B16F10细胞，再使用GSK126治疗。小鼠肝组织切片的H&E和油红O染色显示，GSK126治疗组的脂肪空泡和脂质沉积显著增加(图4A)。小鼠血液中甘油三酸酯(TG)的水平也明显升高(图4B)。这些结果表明，GSK126可以调节肝脏和整个身体的脂质代谢。所以，进一步检测到脂肪酸合成相关基因在GSK126处理的肝癌(HCC)细胞系SMMC7721和Huh7中的表达。如图4C-D所示，在GSK126处理下，ACLY、FASN和SCD的mRNA和蛋白质水平显著升高，这与RNA-seq数据一致。
3.2脂代谢调节药物能够抑制肿瘤细胞的增殖
以前的研究证明这些促进脂肪生成的代谢酶在肿瘤细胞中表现出较强的活性和高表达。并且根据对Oncomine数据库(TCGA_LIHC和GSE8401数据集)进行分析，发现肝癌和黑色素瘤中FASN和ACLY的表达上调(图5A)。同时，ACLY和FASN的高表达分别与肝癌和黑色素瘤患者的不良预后相关(图5B)。上述结果表明脂质合成增加在癌症的发展和进程中起着重要的作用。
PPAR家族是调节葡萄糖和脂质平衡的关键因子，并且PPARα激动剂非诺贝特和PPARγ激动剂替米沙坦(telmisartan)在临床前研究发现具有一定的抗肿瘤疗效。所以，选用替米沙坦和非诺贝特来探究脂代谢调节药物是否具有抗肿瘤效应。通过Incucyte细胞实时监测***，发现替米沙坦以剂量依赖性地方式抑制了人神经胶质瘤细胞U87和U251的增殖(图5C)，非诺贝特也在一定浓度下能够抑制黑色素瘤细胞B16和乳腺癌细胞4T1的增殖(图5D)。还通过EdU染色的方法进一步验证了50μM替米沙坦对细胞增殖的作用。流式细胞术结果显示，替米沙坦治疗后，EdU+的U87细胞的百分比从24.25％降低到21.16％，EdU+的U251细胞的百分比从41.44％降低到38.78％(图5E)。3.3调节脂质代谢可以增强GSK126对癌细胞的抑制作用
由第3.2部分可知，脂质代谢调节药物确实能够抑制细胞的增殖。而且同时观察到GSK126处理后细胞脂质合成增加，这可能解释了为什么在以10μM的GSK126处理后多种肿瘤细胞的敏感性不佳，因此进一步探讨了增加脂肪分解是否可以增强GSK126对癌细胞的抑制作用。由于此前已经有研究表明EZH2和PPARα存在上下游调控关系，并且EZH2和PPARα都在脂质代谢调节过程中发挥了一定作用。所以将GSK126与PPARα激动剂非诺贝特联合用于治疗B16F10和SMMC7721细胞，发现与非诺贝特的联用确实可以显著增强GSK126对细胞增殖的抑制作用(图6A)。同时，还证实了该药物组合可以下调由GSK126治疗引起的脂质代谢升高的水平。发现联合治疗组与GSK126治疗组相比，在B16F10细胞中的脂质代谢基因ATP结合盒式亚家族A成员1(ATP Binding Cassette Subfamily A Member 1，Abca1)和Acsl6的表达显著减少。同时在SMMC7712细胞中，联合治疗组的脂肪酸合成基因(包括ACLY，FASN和SCD1)显著下降(图6B)。
3.4调节脂质代谢可以增强GSK126对脑癌细胞系的抑制作用
3.4.1实验方法
使用IncuCyteLive-Cell Analysis System对小鼠胶质瘤GL261细胞生长情况进行监测和分析。
(1)取对数生长期的GL261细胞制备成单细胞悬液，并进行细胞计数；
(2)分别取8×104个细胞/mL GL261细胞加入96孔培养板中，每个处理组设置4-6个复孔；
(3)将96孔板置于细胞培养箱中继续培养12-24h，待细胞汇合度约为20-30％时，更换含有药物的培养基进行处理。GSK126和非诺贝特(FF)使用培养基进行浓度梯度稀释；
(4)将96孔板置于仪器配套的细胞培养箱中，用IncuCyteLive-CellAnalysis System进行检测。使用10倍物镜以4h的时间间隔，拍摄每孔内4个不同区域的细胞生长图像；
(5)实时监测48h，利用IncuCyte S3图像分析软件，通过界定细胞边缘确定细胞汇合度，标准化0h时间点细胞汇合度并计算百分数，绘制增殖曲线评估细胞增殖情况；
(6)到培养终点时，同时用MTT方法使用分光光度计检测。
3.4.2实验结果
实验结果如图7所示。其中，对照组仅给予溶剂DMSO。实验结果表明，GSK126在40μM浓度时，对小鼠脑胶质瘤细胞系(GL261)的抑制与20μMGSK126和非诺贝特(FF)10μM联用效果一样。而20μM GSK126本身达不到这个效果。即为低剂量GSK与非诺贝特(FF)联可以达到高剂量GSK126才能达到的效果，说明在脑胶质瘤中，两药联合效果更好。
3.5EZH2抑制剂和PPARα激动剂联用在普通荷瘤小鼠模型上的抗肿瘤作用3.5.1构建荷瘤小鼠模型
针对小鼠结肠肿瘤模型：
(1)制备处于对数生长期的小鼠结肠癌肿瘤细胞(MC38)单细胞悬液。利用无菌PBS作溶剂，调整细胞浓度为1.0×107个细胞/mL；
(2)在超净工作台内，6-8周龄的C57BL/6雌性小鼠，体重18-20g，用***钠(40mg/kg)进行麻醉，除毛，以便于荷瘤和肿瘤测量；
(3)利用注射器在小鼠背部右上区域皮下植入MC38细胞(0.1mL的单细胞悬液)，注射局部形成明显的球状凸起；
(4)将小鼠放回饲养笼中，随后观察1-2天。
针对小鼠脑胶质瘤模型：
(1)制备处于对数生长期的小鼠胶质瘤瘤细胞(GL261)单细胞悬液。利用无菌PBS作溶剂，调整细胞浓度为1.0×106个细胞/mL；
(2)在超净工作台内，6-8周龄的C57BL/6雌性小鼠，体重18-20g，用***钠(40mg/kg)进行麻醉，除毛，以便于荷瘤和肿瘤测量；
(3)利用注射器在小鼠背部右上区域皮下植入GL261细胞(0.1mL的单细胞悬液)，注射局部形成明显的球状凸起；
(4)将小鼠放回饲养笼中，随后观察10天。
3.5.2荷瘤小鼠分组和药物治疗
(1)当小鼠背部出现瘤体(约50mm3)后，进行随机分组(5-6只/组，分为对照组和治疗组)和药物治疗；
(2)治疗组分为GSK126单药(50mg/kg/天)、非诺贝特单药(100mg/kg/天)和GSK126(50mg/kg/day)与非诺贝特(100mg/kg/天)联合用药。治疗使用的药物GSK126、非诺贝特购于上海蓝木化工有限公司，溶剂采用说明书配方，对照组使用等量的溶剂处理。给药频率为3次/4天，每2天使用游标卡尺测量和称量天平记录肿瘤的长(a)、宽(b)及小鼠体重变化情况；
(3)药物治疗14天后，处死小鼠并保存相应的组织样本进行下游实验。3.6EZH2抑制剂和PPARα激动剂联用在血脂异常荷瘤小鼠模型上的抗肿瘤作用
3.6.1构建血脂异常小鼠模型
(1)对6-8周龄的C57BL/6雌鼠(体重18-20g)进行随机分组，然后对血脂异常组的小鼠给予市售“西方饮食”小鼠饲料喂养2个月，以构建血脂异常小鼠模型。
(2)血脂异常小鼠的鉴定：采集小鼠眼球血到EP管中，4℃自然凝固。然后2000rpm，4℃离心10min。利用干净的EP管收集血清，低温保存并送至北京大学医学部实验动物科学部进行生化分析(TC、TG、LDL-C、HDL-C等)。
3.6.2在血脂异常小鼠模型的基础上构建荷瘤小鼠模型
(1)制备处于对数生长期的肿瘤细胞(MC38)单细胞悬液。利用无菌PBS作溶剂，调整细胞浓度为1.0×107个/mL；
(2)在超净工作台内，对第3.5.1部分制备的血脂异常小鼠用***钠(40mg/kg)进行麻醉，除毛，以便于荷瘤和肿瘤测量；
(3)利用注射器在小鼠背部右上区域皮下植入MC38细胞(0.1mL的单细胞悬液)，注射局部形成明显的球状凸起；
(4)将小鼠放回饲养笼中，随后观察1-2天。
3.6.3血脂异常荷瘤小鼠分组和药物治疗
(1)当小鼠背部出现瘤体(约50mm3)后，进行随机分组(5-6只/组，分为对照组和治疗组)和药物治疗；
(2)治疗组分为GSK126单药(50mg/kg/天)、非诺贝特单药(100mg/kg/天)和GSK126(50mg/kg/天)与非诺贝特(100mg/kg/天)联合用药。治疗使用的药物GSK126、非诺贝特购于上海蓝木化工有限公司，溶剂采用说明书配方，对照组使用等量的溶剂处理。给药频率为3次/4天，每2天使用游标卡尺测量和称量天平记录肿瘤的长(a)、宽(b)及小鼠体重变化情况；
(3)药物治疗14天后，处死小鼠并保存相应的组织样本进行下游实验。
显然，本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。
Claims (3)
1.一种增强EZH2抑制剂抗肿瘤作用的药物组合物在制备抗肿瘤药物中的用途，其特征在于：所述药物组合物由EZH2抑制剂和PPARα激动剂组成，其中所述PPARα激动剂增强所述EZH2抑制剂抗实体瘤的作用，所述肿瘤是黑色素瘤，所述EZH2抑制剂为10μM GSK126，所述PPARα激动剂为25μM非诺贝特。
2.一种增强EZH2抑制剂抗肿瘤作用的药物制剂在制备抗肿瘤药物中的用途，其特征在于：所述药物制剂由治疗有效量的权利要求1所述的药物组合物和药学上可接受的载体制成，所述肿瘤是黑色素瘤。
3.根据权利要求2所述的用途，其特征在于：所述药物制剂为口服制剂。
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