CN113573725A - 含有if1作为活性成分的抗癌药物组合物 - Google Patents
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Abstract
本发明涉及一种含有IF1(ATP酶抑制因子1)的抗癌组合物。根据本发明的IF1(ATP酶抑制因子1)具有释放细胞外ATP的作用，在各种癌细胞中诱导细胞毒性并表现出抗癌功效，因此作为强大的抗癌剂的活性成分非常有用。
Description
【技术领域】
本发明涉及一种用于提供抗癌活性或抑制癌症转移的组合物，其包含IF1(ATP酶抑制因子1)；更具体地涉及一种用于提供抗癌活性或抑制癌症转移的药物组合物或食品，其包含作为活性成分的IF1，具有抑制癌细胞增殖、增加细胞外ATP释放、抑制癌细胞迁移以及诱导癌症凋亡或癌细胞的自噬的作用。
【背景技术】
由于严重的环境问题和老年人口的增加，全球癌症发病率每年增加超过5％。近年来，癌症死亡人数占所有死亡人数的约四分之一，并且这种趋势正在增加。引起癌症的致癌物包括吸烟、紫外线、化学物质、食品和其他环境因素。然而，由于其原因多种多样，难以开发治疗剂，并且治疗剂的效果也根据发生部位而变化。
目前，手术疗法、化学疗法、生物疗法、放射疗法等被用于癌症治疗。化学疗法也被称为药物疗法，并且使用合成的化学物质，如核酸烷化剂、代谢拮抗剂、天然产物和激素，而生物疗法通过恢复或改善人体的免疫功能削弱癌细胞的活性来预防癌症的进展。细胞因子、免疫治疗药物、基因治疗药物、癌症疫苗、血管生成抑制剂等是可用的。
迄今为止，这些方法已单独或组合应用于治疗，但用作治疗剂的物质具有剧毒，而且此外，由于副作用、耐药性和复发，还没有完美的治疗方法。因此，迫切需要开发一种选择性地仅能够去除癌细胞、预防癌症发生和治疗癌症，并且毒性较小且有效的抗癌剂。
同时，IF1是干扰ATP酶功能的主要蛋白质，并且作为在人体中自然产生并通过线粒体调节ATP的产生与降解的靶标已经对其进行了许多研究(Campanella等人,CellMetab,8:13-25,2008)。IF1在各种细胞和与其对应的癌细胞中过表达，但每种细胞系的模式不同。这意味着IF1对人体的影响可能以组织特异性方式变化。使用靶向IF1蛋白的抗体进行的先前研究的结果显示，在胃、心脏、肝脏、子宫内膜和肾脏的上皮细胞中表达高水平的IF1。与此不同，与正常细胞相比，胃、肺、乳腺、结肠和卵巢细胞中的IF1水平趋于在癌细胞中显著增加。然而，IF1在基因水平上的表达水平并未显示出与上述相同的行为。在结肠和乳腺中，与正常细胞中的表达水平相比，癌细胞中IF1 mRNA的表达水平增加，但在肺和卵巢中，正常细胞中的表达水平更高(Maria等人,Oncogenesis 2.4:e46,2013；Laura等人,Journal of Biological Chemistry,jbc-M110,2010)
此外，据报道，作为IF1靶标的ATP酶在各种细胞类型的细胞膜以及线粒体中表达。具体而言，ATP酶存在于HUVEC、BCE(牛眼睛)、A549(肺癌)、SNU-C5(人胃)、THP-1(单核细胞)、HepG2(肝)、CEM(人白血病细胞)、BAEC(牛主动脉内皮细胞)、杏仁核、成神经细胞瘤B103、C6星形细胞瘤、Daudi(人淋巴瘤)、成纤维细胞、MOLT-4T细胞、3T3-L1、HaCaT(永生角质形成细胞)、乳腺癌、143B(骨肉瘤)、293T(肾脏)、心脏、脾脏、胸腺和骨骼肌中(Lyly,Annina等人,Human molecular genetics 17.10:1406-1417,2008)。由于上述所有细胞系和组织均具有不同的ATP酶亚基，因此IF1的注射将影响人体中每种组织功能的变化。换句话说，IF1与细胞膜中的F1-ATP酶结合并抑制所述酶对ATP的降解，从而导致细胞外ATP(exATP)的量增加，并且可以预期增加的exATP将通过触发相关嘌呤信号传导的机制对癌症发挥预防或治疗作用。
因此，作为开发没有副作用但表现出优异效果的癌症治疗剂的广泛努力的结果，诸位发明人发现，IF1重组蛋白在多种癌细胞中具有抑制癌细胞增殖、增加细胞外ATP释放、抑制癌细胞迁移以及诱导癌细胞的凋亡或自噬的作用。基于此发现，完成了本发明。
【发明内容】
【技术问题】
因此，鉴于上述问题完成了本发明，并且本发明的一个目的是提供一种用于提供抗癌活性或抑制癌症转移的药物组合物或食品，其包含作为活性成分的IF1，具有通过抑制癌细胞增殖、增加细胞外ATP释放、抑制癌细胞迁移以及诱导癌细胞的凋亡(细胞死亡)或自噬来激活免疫系统、提供抗癌活性和抑制癌症转移的作用。
【技术方案】
根据本发明的一个方面，上述和其他目的可以通过提供一种用于提供抗癌活性或抑制癌症转移的含有IF1(ATP酶抑制因子1)作为活性成分的药物组合物来实现。
根据本发明的另一个方面，提供了一种用于提供抗癌活性或抑制癌症转移的功能性食品，其含有IF1(ATP酶抑制因子1)作为活性成分。
根据本发明的另一个方面，提供了一种用于预防或治疗癌症或抑制癌症转移的方法，其包括向受试者施用IF1(ATP酶抑制因子1)。
根据本发明的另一个方面，提供了IF1(ATP酶抑制因子1)用于预防或治疗癌症或抑制癌症转移的用途。
根据本发明的另一个方面，提供了包含作为活性成分的IF1(ATP酶抑制因子1)的药物组合物用于预防或治疗癌症或抑制癌症转移的用途。
根据本发明的另一个方面，提供了IF1(ATP酶抑制因子1)用于制造预防或治疗癌症或抑制癌症转移用的药物的用途。
【附图说明】
图1示出了IF1处理后肝癌和乳腺癌细胞系中细胞外ATP释放的增加。在与基础水平进行比较后，*p<0.01是满意的。
图2示出了MTT和CVS分析的结果，示出了IF1处理对四种癌细胞系增殖的抑制作用，其中(A)和(B)示出了在24小时和48小时通过MTT分析得到的4种细胞系的结果，(C)示出了在MDA-MB-231乳腺癌细胞系中在6、24和48小时的MTT分析结果，并且(D)示出了使用CVS分析在IF1处理后48小时测量的相对细胞活力。在与相应的对照组进行比较后，*p<0.05、**p<0.01、***p<0.001和***p<0.0001是满意的。
图3示出了在迁移测定时用IF1(1ug/ml、10ug/ml)处理48小时以确定IF1处理对癌细胞迁移的抑制作用的结果。
图4示出了半胱天冬酶3/7活性的增加，显示通过IF1处理诱导凋亡。在与每个对照组进行比较后，*p<0.05、**p<0.01、***p<0.001和***p<0.0001是满意的。
图5示出了蛋白质印迹的结果，显示IF1导致的(A)Akt和mTOR活性的降低以及(B)LC3B蛋白表达的降低。
图6示出了使用PI3K抑制剂测定IF1的通过PI3K的细胞增殖抑制和凋亡作用。
图7示出了sXBP1的表达水平，表明通过IF1诱导ER应激。在与每个对照组进行比较后，*p<0.05、**p<0.01、***p<0.001和****p<0.0001是满意的。
【具体实施方式】
除非另外定义，否则本文所用的所有技术和科学术语都具有与由本发明所涉及领域的技术人员所理解的含义相同的含义。通常，本文所用的命名法是本领域中熟知的，并且是通常使用的。
ATP酶抑制因子1(在下文称为“IF1”)是由84个氨基酸组成的9.6kDa碱性蛋白，并且由ATP5IF1基因编码。ATP酶由F0和F1结构域以及中央和外围茎组成，并且细分为多个亚基。IF1与参与线粒体中ATP的合成和降解的F1Fo ATP合酶(多亚基膜结合组装体)结合。IF1与位于质膜中的F1-ATP酶亚基结合。此时，ATP水解被F1-ATP酶活性的调节抑制，从而引起细胞外ATP(exATP)的增加。IF1在缺氧期间与F1Fo ATP合酶结合，并且抑制ATP降解，从而防止ATP损失并因此抑制凋亡。此外，已知在癌细胞等中观察到的内源性IF1的过表达和F1FoATP合酶的表达降低有助于能量代谢重编程，如增加的糖酵解。如上所述，在具有线粒体功能减退作为病理生理学的疾病中观察到IF1的过表达和F1Fo ATP合酶的表达降低，但尚无通过从外部来源注射IF1来预防或治疗癌症的已知机制。
免疫力改善在预防癌症的机制中起着重要作用，而IF1导致的exATP增加有望在免疫系统的激活中起关键作用。exATP浓度的增加在人体内表现得像危险信号，通过单核细胞的P2Y2受体的活性引起吞噬，或使用Toll样受体(TLR)或NOD样受体(NLR)激活免疫系统。关于炎症小体募集，已经观察到炎症小体通过经由NLRP3(或NALP3)P2X7(其下游)的嘌呤信号传导的激活，其通过先天免疫系统诱导促炎细胞因子(如IL-1β)的半胱天冬酶-1依赖性成熟(Piccini,Alessandra等人,PNAS 105.23:8067-8072,2008)。因此，可以看出，从外部注射IF1通过从相应细胞的细胞膜释放ATP来调节免疫系统，从而执行旁分泌和自分泌两种功能。由于免疫细胞B细胞的增殖、NK细胞的迁移以及T细胞的免疫反应也受到exATP的调节，因此预期用IF1治疗可预防使用免疫反应作为机制的各种癌，并且使得嘌呤系统信号传导对使用免疫系统的癌症治疗能够具有有益作用。
因此，在本发明中，通过基于整个小鼠IF1 mRNA序列(NCBI编号NM_007512.3)克隆IF1的DNA数据产生了包含GST标签的重组蛋白(SEQ ID NO:1)，并且用重组IF1处理一些癌细胞系(肝癌细胞系，HepG2；乳腺癌细胞系，MDA-MB-231、T47D；宫颈癌细胞系，HeLa)以确定对癌细胞的增殖和凋亡的抑制。此外，证明了在用IF1处理癌细胞后，培养基中的ATP浓度显著增加，并且癌细胞的迁移受到抑制。
因此，在一个方面，本发明涉及用于提供抗癌活性或抑制癌症转移的药物组合物，其含有IF1(ATP酶抑制因子1)作为活性成分。
如本文所用，术语“抗癌”包括“预防”和“治疗”，并且术语“预防”是指通过施用根据本发明的药物组合物可以抑制或延迟癌症发作的任何作用。如本文所用，术语“治疗”或“治疗性”是指通过施用根据本发明的药物组合物可以改善或有利地改变癌症症状的任何作用。
如本文所用，术语“转移”是指癌症或恶性肿瘤从其形成的器官扩散到与其间隔开的另一组织的状态。
在本发明中，IF1通过抑制癌细胞的增殖、增加癌细胞的细胞外ATP的释放、抑制癌细胞的迁移或诱导癌细胞的凋亡或自噬而表现出抗癌活性或癌症转移抑制活性。可以看出，ATP的细胞外释放通过激活免疫系统而表现出抗癌活性。
在本发明中，所述癌症包括一般癌症疾病，并且优选地选自肝癌、乳腺癌、子宫癌、宫颈癌、肺癌、非小细胞肺癌、结直肠癌、前列腺癌、胰腺癌、胃癌、食管癌、卵巢癌、骨癌、腺癌、膀胱癌、肾癌、输尿管癌、支气管癌、鼻咽癌、喉癌、脑肿瘤、脊髓肿瘤、血癌、直肠癌、皮肤癌、头癌、头颈癌、黑色素瘤、小肠癌、结肠癌、肛门癌、输卵管癌、子宫内膜癌、阴道癌、外阴癌、霍奇金病、淋巴腺癌、胆囊癌、内分泌腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病、淋巴细胞性淋巴瘤、肾盂癌、脑癌、中枢神经系统(CNS)肿瘤、脑干胶质瘤和垂体腺瘤，但不限于此。
本发明的药物组合物可以以药学有效量施用。本文使用的术语“药学有效量”意指足以以适用于医学治疗或预防的合理效益/风险比治疗或预防疾病的量。有效量根据包括以下的因素来确定：疾病的严重程度、药物的活性、患者的年龄、体重、健康和性别、患者对药物的敏感性、施用时间、施用途径、和所使用的本发明组合物的排泄速率和治疗期、与本发明组合物组合或同时使用的药物、以及药学领域熟知的其他因素。
本发明的药物组合物可以作为单一治疗剂施用或与其他治疗剂组合顺序或同时施用。本发明的药物组合物可以以单个或多个剂量施用。考虑到这些因素，重要的是在不产生副作用的情况下以足以实现最大功效的最小量施用组合物。
此外，根据本发明的药物组合物的剂量(施用量)可以由本领域技术人员考虑使用目的、疾病的严重程度、患者的年龄、体重、性别和病史、用作活性成分的物质的类型等来决定。例如，可以将药物组合物以10mg/kg至100mg/kg、更优选10mg/kg至30mg/kg的日剂量施用至成人。本发明的组合物的施用频率没有特别限制，并且可以将组合物一天施用一至三次，或者可以分为多个剂量并全天施用。
本发明的药物组合物可以按用于治疗或预防癌症的药物组合物的形式来制备，所述药物组合物还含有通常用于制备药物组合物的适当载体、赋形剂或稀释剂，并且所述载体可以包括非天然存在的载体。
具体而言，药物组合物可以根据常规方法按以下形式来配制：口服配制品，如粉末、颗粒、片剂、胶囊、悬浮液、乳液、糖浆或气溶胶；外用制剂；栓剂；或无菌可注射溶液。
药物组合物中所包含的载体、赋形剂或稀释剂的具体例子包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓醇、麦芽糖醇、淀粉、阿拉伯树胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、硬脂酸镁、矿物油等。在配制品的情况下，药物组合物可以使用稀释剂或赋形剂如常用的填充剂、增量剂、粘合剂、润湿剂、崩解剂或表面活性剂来制备。
用于口服施用的固体配制品可以包括片剂、丸剂、粉末、颗粒、胶囊等，并且可以通过将至少一种赋形剂(例如，淀粉、碳酸钙、蔗糖、乳糖、明胶等)混合来制备。除了简单赋形剂以外，还使用润滑剂，如硬脂酸镁和滑石粉。
用于口服施用的液体配制品可以是悬浮液、口服液体和溶液、乳液、糖浆等，并且可以含有各种赋形剂，如润湿剂、甜味剂、香味剂、防腐剂等，以及水和液体石蜡(它们是常用的简单稀释剂)。用于肠胃外施用的配制品可以包括灭菌的水性溶液、非水性溶剂、悬浮液、乳液、冷冻干燥的制剂和栓剂。非水性溶剂和悬浮液的例子包括丙二醇、聚乙二醇、植物油如橄榄油、可注射酯如油酸乙酯等。
药物组合物可以呈无菌可注射制剂的形式，如无菌可注射水性或油性悬浮液。可以根据本领域已知的技术使用合适的分散剂或润湿剂(例如，Tween80)和悬浮剂来配制这种悬浮液。无菌可注射制剂也可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液(例如，在1,3-丁二醇中的溶液)。可用的可接受的媒介物和溶剂可以包括甘露醇、水、林格氏溶液和等渗氯化钠溶液。此外，通常使用无菌非挥发性油作为溶剂或悬浮介质。为此，也可以使用任何刺激性较小的含有合成单甘油酯或二甘油酯的非挥发性油。脂肪酸(如油酸)及其甘油酯衍生物可用于可注射制剂，像药学上可接受的天然油(例如，橄榄油或蓖麻油)，特别是其聚氧乙基化形式。
本发明的药物组合物也可以按用于直肠施用的栓剂形式施用。这些组合物可以通过将本发明的化合物与合适的无刺激性赋形剂混合来制备，所述赋形剂在室温下为固体，但在直肠温度下为液体。此类材料包括但不限于可可脂、蜂蜡和聚乙二醇。
当所需的治疗涉及通过局部施用易于接近的部位或器官时，根据本发明的药物组合物的肠胃外施用特别有用。当局部涂抹至皮肤时，应当将药物组合物配制为含有悬浮或溶解在载体中的活性成分的合适的软膏。用于本发明化合物的局部施用的载体包括但不限于矿物油、液体石蜡、白凡士林、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。可替代地，可以将药物组合物配制为含有悬浮或溶解在载体中的活性化合物的合适洗剂或乳膏。合适的载体包括但不限于矿物油、脱水山梨醇单硬脂酸酯、聚山梨醇酯60、鲸蜡基酯蜡、鲸蜡硬脂醇、2-辛基十二烷醇、苯甲醇和水。本发明的药物组合物也可以按直肠栓剂或合适的灌肠剂的形式局部施用至下肠道。局部施用的透皮贴剂也落入本发明的范围内。
本发明的药物组合物可以作为鼻气溶胶或通过吸入施用。这种组合物是根据药物领域熟知的技术来制备的，并且使用苯甲醇或其他合适的防腐剂、增强生物利用度的吸收促进剂、碳氟化合物和/或本领域已知的其他增溶剂或分散剂制备成盐水溶液。
本发明药物组合物中所包含的药剂的含量并不特别限制于此，但基于最终组合物的总重量，可以是按重量计0.0001％至50％，更优选按重量计0.01％至10％。
在另一个方面，本发明涉及用于预防或治疗癌症或抑制癌症转移的方法，其包括向受试者施用IF1(ATP酶抑制因子1)。
在另一个方面，本发明涉及IF1(ATP酶抑制因子1)用于预防或治疗癌症或抑制癌症转移的用途。
在另一个方面，本发明涉及包含作为活性成分的IF1(ATP酶抑制因子1)的药物组合物用于预防或治疗癌症或抑制癌症转移的用途。
在另一个方面，本发明涉及IF1(ATP酶抑制因子1)用于制备预防或治疗癌症或抑制癌症转移用的药物的用途。
如本文所用，术语“受试者”是指患有癌症或有患上癌症风险的任何动物，包括人，并且所述疾病可以通过向其施用根据本发明的组合物来有效地预防或治疗。
癌症治疗适用于可能患有癌症的任何哺乳动物，包括但不限于人和灵长类动物以及家畜(如牛、猪、羊、马、狗和猫)，但优选人。
如本文所用，术语“施用”是指通过任何适当的方法将根据本发明的药物组合物引入受试者中的动作，并且组合物的施用途径可以是任何一般途径，只要所述途径使得能够将组合物递送至靶组织。药物组合物可以腹膜内、静脉内、肌肉内、皮下、皮内、口服、局部、鼻内、肺内或经直肠施用，但不限于此。
在另一个方面，本发明涉及用于提供抗癌活性或抑制癌症转移的功能性食品，其含有IF1(ATP酶抑制因子1)作为活性成分。
如本文所用，术语“抗癌”包括“预防”和“改善”，并且术语“预防”是指通过施用根据本发明的药物组合物可以抑制或延迟癌症发作的任何作用。如本文所用，术语“改善”是指至少降低与待治疗的病症相关的参数的严重程度(例如，症状的严重程度)的任何作用。
如本文所用，术语“转移”是指癌症或恶性肿瘤从其形成的器官扩散到与其间隔开的另一组织的状态。
在本发明中，IF1通过抑制癌细胞的增殖、增加癌细胞的细胞外ATP的释放、抑制癌细胞的迁移或诱导癌细胞的凋亡或自噬而表现出抗癌活性或癌症转移抑制活性。可以看出，ATP的细胞外释放通过激活免疫系统而表现出抗癌活性。
在本发明中，所述癌症包括一般癌症疾病，并且优选地选自肝癌、乳腺癌、子宫癌、宫颈癌、肺癌、非小细胞肺癌、结直肠癌、前列腺癌、胰腺癌、胃癌、食管癌、卵巢癌、骨癌、腺癌、膀胱癌、肾癌、输尿管癌、支气管癌、鼻咽癌、喉癌、脑肿瘤、脊髓肿瘤、血癌、直肠癌、皮肤癌、头癌、头颈癌、黑色素瘤、小肠癌、结肠癌、肛门癌、输卵管癌、子宫内膜癌、阴道癌、外阴癌、霍奇金病、淋巴腺癌、胆囊癌、内分泌腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、慢性或急性白血病、淋巴细胞性淋巴瘤、肾盂癌、脑癌、中枢神经系统(CNS)肿瘤、脑干胶质瘤和垂体腺瘤，但不限于此。
如本文所用，术语“功能性食品”是指使用物理、生物化学和生物技术等赋予附加价值以作用于和表达食品用于特定目的的功能的一组食品，或被设计和加工以充分表达食品组合物的身体控制功能(如生物防御节律控制、疾病预防和体内疾病恢复)的食品，并且具体而言，所述功能性食品可以是保健功能性食品。
当本发明的食品组合物用作食品添加剂时，所述食品组合物可以单独或与其他食品或食品添加剂组合使用，并且可以根据常规方法合适地使用。通常，当制备食品或饮料时，基于原料，以按重量计15％或更少、优选按重量计10％或更少的量添加本发明的组合物。然而，在出于健康和卫生目的或出于健康管理目的而长期摄入的情况下，所述量可以低于上文定义的范围，但是将明显的是，所述活性成分的使用量可以超过上述范围，因为在安全性方面没有问题。
本发明的食品可以按任何形式制备，如功能性食品、营养补充剂、保健食品或食品添加剂。例如，作为保健食品的本发明的组合物可以被制备成茶、果汁或饮料的形式以供饮用，或者可以被颗粒化、胶囊化和粉末化以供摄入。此外，功能性食品可以通过将本发明的组合物添加到以下中来制备：饮料(包括酒精饮料)、水果及其加工食品(例如，罐装水果、瓶装水果、果酱、柑橘酱等)、鱼、肉及其加工食品(例如，火腿、香肠、咸牛肉等)、面包和面条(例如，乌冬面、荞麦面、拉面、意大利面、通心粉等)、果汁、各种饮品、饼干、Yeot(韩国硬太妃糖)、乳制品(例如，黄油、奶酪等)、食用植物油、人造黄油、植物蛋白、装在蒸煮袋中的食品、冷冻食品、各种调味料(例如，味噌、酱油、沙司等)等。
所述保健功能性食品包括作为食品组合物的各种形式，如功能性食品、营养补充剂、保健食品、食品添加剂等，并且所述保健功能性食品可以通过以下来提供：根据本领域已知的常规方法，将本发明的组合物制备成各种形式，如茶、果汁或饮品，或者进行颗粒化、胶囊化或粉末化，或者将这些化合物或提取物添加到各种食品如饮料、水果和加工食品、鱼、肉和加工食品、面包、面条、调味料等中。
健康饮料组合物可以含有另外的成分，如各种风味剂或天然碳水化合物，就像一般饮料一样。天然碳水化合物包括单糖(如葡萄糖和果糖)、二糖(如麦芽糖和蔗糖)以及天然甜味剂(如糊精和环糊精)。此外，可以使用合成甜味剂，如糖精和阿斯巴甜。天然碳水化合物的比例可以由本领域技术人员适当地选择。
除了上述成分以外，本发明的组合物还可以含有各种营养素、维生素、电解质、调味剂、着色剂、果胶酸及其盐、藻酸及其盐、有机酸、保护性胶体增稠剂、pH调节剂、稳定剂、防腐剂、甘油、醇、碳酸饮料中使用的碳酸化剂等。此外，本发明的组合物可以含有用于生产天然果汁、果汁饮料和蔬菜饮料的果肉。这些组分可以单独或组合使用。这些添加剂的比例也可以由本领域技术人员适当地选择。
实施例
在下文中，将参考实施例更加详细地描述本发明。然而，对于本领域技术人员而言将明显的是，这些实施例的提供仅用于说明本发明，并且不应当解释为限制基于本发明的主题的本发明的范围。
实施例1：细胞外ATP释放的测量
将乳腺癌(MDA-MB-231、MCF7、T47D)、肝癌(HepG2)和宫颈癌(HeLa)细胞系在含有10％FBS和1％青霉素/链霉素的DMEM培养基中于5％二氧化碳下在37℃的培养箱中孵育。
使用CellTiter-Glo发光测定试剂盒(Promega，美国威斯康星州麦迪逊)测量用IF1处理后的细胞外ATP释放。将HepG2(肝癌细胞系)或MDA-MB-231(乳腺癌细胞系)细胞(3×104个细胞/孔)用IF1(100ng/mL)处理，然后在37℃和5％CO2的条件下在培养箱中的1％BSA/DMEM培养基中孵育10秒、30秒、1分钟、5分钟、10分钟和30分钟。然后，收获每种培养基，并且进行发光测定。
结果，可以看出，在用IF1处理后，培养基中的ATP浓度快速增加(图1)。可以看出，这种增加在HepG2细胞的情况下在约5分钟的持续时间后并且在MDA-MB-231细胞的情况下在约10分钟的持续时间后恢复到基础水平。
实施例2：体外癌细胞增殖和死亡测定
为了研究IF1在癌细胞中的细胞毒性和增殖抑制作用，进行了MTT(3-(4,5-二甲基噻唑基-2)-2,5-二苯基四唑鎓溴化物)测定和CVS(结晶紫溶液)测定。MTT和CVS测定是测量活细胞生长的方法。MTT使用通过活细胞的线粒体还原酶进行的MTT还原，而CVS使用以下现象来测量细胞的活力：其中细胞在死亡后与板分离，由此结晶紫染色水平降低。
将每个癌细胞系(HepG2、MDA-MB-231、T47D、HeLa)接种到96孔板中，并且在37℃和5％CO2的条件下在培养箱中孵育过夜，然后在第二天再次在新鲜的无血清培养基中孵育过夜。除了对照组之外，在6h、24h和48h用各种浓度的IF1处理细胞(MDA-MB-231细胞系)。在完成用IF1处理后，用PBS洗涤板两次，并且向每个孔中添加200μl比率为1:40的MTT溶液和培养基的混合物。将板用箔包裹以阻挡光线，并且在37℃和5％CO2的条件下储存在培养箱中，直到板的底部变成紫色。然后，除去MTT溶液，向每个孔中添加200μl DMSO，并且允许孔在室温下于振动器上静置5分钟。将每个孔中的溶液再次转移到新鲜板中，并且通过ELISA读取器在570nm处测量吸光度，以计算相对于对照细胞的100％的相对细胞增殖抑制。
结果显示，由于用IF1处理，所有四种类型的癌细胞系(HepG2、MDA-MB-231、T47D、HeLa)在24h和48h时均表现出细胞增殖的显著降低(图2A和2B)。此外，从24h至48h，MDA-MB-231乳腺癌细胞系表现出细胞增殖的显著降低(图2C)。
通过CVS染色进一步评价了MDA-MB-231乳腺癌细胞系的细胞活力。在24小时后，除去培养基，将IF1(500nM、1μM)添加到含有0.5％FBS的DMEM培养基中，并且将接种在12孔板上的乳腺癌细胞在37℃和5％CO2下孵育48小时。然后，使用25％甲醇和0.5％结晶紫溶液对细胞染色。用PBS洗涤细胞三次，然后测量溶解在1％SDS中的溶液在570nm处的吸光度，并且重复三次以获得平均值。
结果显示，与对照相比，细胞增殖在48h时以IF1浓度依赖性方式降低(图2D)。
实施例3：用IF1处理对癌细胞迁移的抑制作用
人体中的癌细胞通过其特征和微环境的组成迁移到健康组织并引起转移。癌细胞的转移意味着正常组织向癌组织的转化。因此，通过细胞迁移实验观察IF1对癌细胞的作用。
在一个方向上刮取每个孔，然后用不同浓度的IF1处理在6孔板中培养的MDA-MB-231细胞，并且在48小时用光学显微镜观察。
结果显示，随着IF1浓度的增加，迁移到空白空间的细胞数量减少，这表明IF1抑制了癌细胞的迁移(图3)。
实施例4：凋亡的测量
进行了半胱天冬酶3/7活性测试以确认凋亡与IF1的抗癌作用之间的关系。半胱天冬酶是一种被细胞外和细胞内因子激活以促进与凋亡有关的酶的反应的蛋白质，并且半胱天冬酶3/7的活性是与凋亡直接相关的主要标记物。
将接种在96孔板上的MDA-MB-231细胞用含有IF1和0.5％FBS的DMEM处理并培养48小时。使用来自Promega的半胱天冬酶-Glo 3/7测定试剂盒允许结果在室温下反应30分钟，然后使用光度计测量发光。
通过重复实验获得的数据平均值的分析结果显示，用IF1处理通过增加半胱天冬酶3/7活性来诱导凋亡，从而降低乳腺癌细胞的存活(图4)。
实施例5：细胞自噬的测量
为了确认IF1的抗癌作用与自噬之间的关系，进行了蛋白质印迹和MTT测定。mTOR是参与细胞生长的蛋白激酶之一，并且是与自噬有关的主要因子。当细胞处于应激环境时或当营养供应困难时，mTOR在细胞内受到调节。特别地，已知其受到响应于细胞外部刺激的PI3K/AKT信号传导通路的抑制。
为了阐明IF1与自噬相关因子之间的相关性，通过蛋白质印迹检测了S6(mTOR复合物组分)、AKT和LC3B蛋白在MDA-MB-231乳腺癌细胞系中的磷酸化和表达水平。
结果显示，用IF1处理在48小时后抑制了Akt和S6蛋白的磷酸化，从而降低了其活性(图5A)。还观察到自噬标记物LC3B的表达水平降低(图5B)。
此外，为了观察自噬对IF1的抗癌活性的影响，在实施例1中进行的MTT测定中，用IF1和PI3K/AKT的抑制剂LY294002同时处理MDA-MB-231乳腺癌细胞系。
结果显示，用LY294002处理有效地抑制了IF1的抗癌活性，这表明由mTOR调节的自噬活性是IF1信号传导通路的靶标(图6)。
实施例6：通过用IF1处理诱导ER应激
ER(内质网)是一种细胞器，其通过负责细胞内蛋白质的折叠、修饰和运输而在维持体内平衡方面发挥重要作用。最近，当ER应激发生在癌细胞中时，已知会诱导凋亡和自噬，因此引起人们的关注。ER应激的诱导通过UPR(未折叠蛋白反应)引起抗癌活性。此时，通过以下现象来实现信号传导：其中XBP1通过RNA酶作用被切割，从而转化为sXBP1。
因此，为了确定IF1与ER应激之间的关系，用IF1将MDA-MB-231乳腺癌细胞系处理6h、24h和48h，以观察sXBP1的mRNA表达水平(图7)。
结果显示，在6h和24h时，sXBP1的表达与对照组相比显著增加，这表明IF1的抗癌作用与ER应激有关。
【工业实用性】
根据本发明的IF1(ATP酶抑制因子1)在多种癌细胞中具有抑制癌细胞增殖、增加细胞外ATP释放、抑制癌细胞迁移以及诱导癌细胞的凋亡或自噬的作用，因此表现出抗癌活性或抑制癌症转移的活性，因此作为抗癌药物的有效活性成分非常有用。
尽管已经详细描述了本发明的具体配置，但本领域技术人员应理解，出于说明目的提供本说明书以阐述优选实施方案，并且不应当解释为限制本发明的范围。因此，本发明的实质范围由所附权利要求及其等同物限定。
【序列表自由文本】
附有电子文件。
<110> 高丽大学校产学协力团
<120> 含有IF1作为活性成分的抗癌药物组合物
<130> PP-B2276
<150> KR 10-2018-0117694
<151> 2018-10-02
<160> 1
<170> KoPatentIn 3.0
<210> 1
<211> 81
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组IF1
<400> 1
Val Ser Asp Ser Ser Asp Ser Met Asp Thr Gly Ala Gly Ser Ile Arg
1 5 10 15
Glu Ala Gly Gly Ala Phe Gly Lys Arg Glu Lys Ala Glu Glu Asp Arg
20 25 30
Tyr Phe Arg Glu Lys Thr Lys Glu Gln Leu Ala Ala Leu Arg Lys His
35 40 45
His Glu Asp Glu Ile Asp His His Ser Lys Glu Ile Glu Arg Leu Gln
50 55 60
Lys Gln Ile Glu Arg His Lys Lys Lys Ile Gln Gln Leu Lys Asn Asn
65 70 75 80
His
Claims (10)
1.一种用于提供抗癌活性或抑制癌症转移的药物组合物，其包含IF1(ATP酶抑制因子1)作为活性成分。
2.根据权利要求1所述的药物组合物，其中所述IF1通过抑制癌细胞的增殖、增加癌细胞的细胞外ATP释放、抑制癌细胞的迁移以及诱导癌细胞的凋亡或自噬来提供抗癌活性或抑制癌症转移的活性。
3.根据权利要求2所述的药物组合物，其中细胞外ATP释放激活免疫系统。
4.根据权利要求1所述的药物组合物，其中所述癌症选自肝癌、乳腺癌、子宫癌、宫颈癌、肺癌、非小细胞肺癌、结直肠癌、前列腺癌、胰腺癌、胃癌、食管癌、卵巢癌、骨癌、腺癌、膀胱癌、肾癌、输尿管癌、支气管癌、鼻咽癌、喉癌、脑肿瘤、脊髓肿瘤和血癌。
5.根据权利要求1所述的药物组合物，其还包含药学上可接受的载体、赋形剂或稀释剂。
6.一种用于提供抗癌活性或抑制癌症转移的功能性食品，其包含IF1(ATP酶抑制因子1)作为活性成分。
7.根据权利要6所述的功能性食品，其中所述IF1通过抑制癌细胞的增殖、增加癌细胞的细胞外ATP释放、抑制癌细胞的迁移以及诱导癌细胞的凋亡或自噬来提供抗癌活性。
8.根据权利要7所述的功能性食品，其中细胞外ATP释放激活免疫系统。
9.根据权利要6所述的功能性食品，其中所述癌症选自肝癌、乳腺癌、子宫癌、宫颈癌、肺癌、非小细胞肺癌、结直肠癌、前列腺癌、胰腺癌、胃癌、食管癌、卵巢癌、骨癌、腺癌、膀胱癌、肾癌、输尿管癌、支气管癌、鼻咽癌、喉癌、脑肿瘤、脊髓肿瘤和血癌。
10.根据权利要求6所述的功能性食品，其还包含营养学上可接受的食品补充添加剂。
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| CN110604744A (zh) * | 2019-09-29 | 2019-12-24 | 新乡医学院 | Atpif1基因沉默的t细胞在制备抗肿瘤药物中的应用 |
| CN114752615A (zh) * | 2022-04-21 | 2022-07-15 | 新乡医学院 | 过表达atp5if1基因的靶向cd19的car-t细胞及其应用 |
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| CN114752615A (zh) * | 2022-04-21 | 2022-07-15 | 新乡医学院 | 过表达atp5if1基因的靶向cd19的car-t细胞及其应用 |
| CN114752615B (zh) * | 2022-04-21 | 2023-09-22 | 新乡医学院 | 过表达atp5if1基因的靶向cd19的car-t细胞及其应用 |
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