CN113712949B - 正辛酸在制备预防和/或治疗肿瘤产品中的应用 - Google Patents
正辛酸在制备预防和/或治疗肿瘤产品中的应用 Download PDFInfo
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- CN113712949B CN113712949B CN202111080558.1A CN202111080558A CN113712949B CN 113712949 B CN113712949 B CN 113712949B CN 202111080558 A CN202111080558 A CN 202111080558A CN 113712949 B CN113712949 B CN 113712949B
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Abstract
本发明涉及正辛酸在制备预防和/或治疗肿瘤产品中的应用。肺腺癌是一种起源于支气管的周围型肺病，早期没有明显的临床症状，发现时通常为晚期。本发明目的在于进一步筛选具有抗肿瘤活性的小分子实体化合物，经研究确认，正辛酸具有良好的抗肺腺癌活性，体外研究中可以有效抑制肺腺癌的生长、转移和侵袭，并且能够通过抑制炎症因子的表达辅助改善抗癌效果，有望成为一种具有良好开发前景的小分子化合物。
Description
技术领域
本发明属于抗肿瘤活性成分技术领域，具体涉及正辛酸作为一种肿瘤抑制活性成分在制备预防和/或治疗肿瘤产品中的应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解，而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
肿瘤具有增殖激活、逃避凋亡、炎症反应、侵袭转移等十大特征。炎症反应在肿瘤复杂病理机制中发挥主导作用，炎症细胞会造成DNA损伤，使抑癌基因发生突变，导致肿瘤的发生；炎症细胞分泌的生长因子可与肿瘤细胞上的受体结合，促进肿瘤细胞生存和增殖，同时还能够招募其他炎症细胞至肿瘤微环境中，促使细胞增殖并诱导血管生成，从而促进肿瘤的生长；炎症反应还会加速肿瘤细胞侵入血液，形成转移灶，与炎症细胞及间质细胞相互作用，促进肿瘤细胞在转移位的生长。研究表明，抑制肺部炎症反应能抑制肺腺癌细胞增殖，减少肺腺癌的数量和体积；持续的肺部炎症导致休眠肿瘤细胞周围区域形成网状结构，酶位点暴露，诱导休眠的癌细胞重新苏醒并开始增殖；巨噬细胞增强癌细胞炎症反应，在肺内积聚是引起肺癌的主要原因；晚期非小细胞肺癌患者全身炎症水平升高与卡铂化疗后生存期明显缩短有关。由以上可知，肺癌发生发展与炎症反应密切相关，调控炎症反应是干预肺癌的重要手段。
肺腺癌(lung adenocarcinoma)是肺癌的一种，属于非小细胞癌。不同于鳞状细胞肺癌，肺腺癌较容易发生于女性及不抽烟者。起源于支气管粘膜上皮，少数起源于大支气管的粘液腺。发病率比鳞癌和未分化癌低，发病年龄较小，女性相对多见。多数腺癌起源于较小的支气管，为周围型肺癌。早期一般没有明显的临床症状，往往在胸部X线检查时被发现。表现为圆形或椭圆形肿块，一般生长较慢，早期一般没有明显的临床症状，往往在胸部X线检查时被发现。表现为圆形或椭圆形肿块，一般生长较慢，但有时早期即发生血行转移。淋巴转移则发生较晚。肺腺癌会导致支气管阻塞，原本正常肺泡囊腔消失，影响氧气与二氧化碳的交换，病人会因此感到胸闷、气短；如果肺癌得不到及时的控制，急速恶化下去，对患者的生命产生极大的威胁。
针对肺腺癌的化药开发中，小分子药物结构具有良好的空间分散性，其化学性质决定了其良好的成药性能和药物代谢动力学性质。这些特点就使得小分子药物在药物研发过程及其它药物领域中表现出巨大优势，小分子药物研发越来越受到市场的青睐。
正辛酸，为无色透明油状液体，有汗臭，微溶于热水，溶于乙醇、苯、乙醚。用于制染料、药物、香料、增塑剂、润滑剂、防腐剂、杀菌剂等。脂肪酸能够通过抑制NF-κB通路，进而抑制炎症反应，另外还可以通过抑制转化生长因子激活激酶-1(transforming growthfactor activated kinase-1,TAK1)的活化，阻止下游信号分子激活NF-κB进而抑制炎症反应，正辛酸作为中链脂肪酸，对炎症的相关作用及对肿瘤细胞的迁移作用尚未研究。
发明内容
基于上述技术背景，本发明目的在于进一步扩展抗肿瘤活性成分，提供具有开发前景的实体小分子化合物。
为了实现上述技术目的，本发明提供以下技术方案：
本发明第一方面，提供正辛酸在制备预防和/或治疗肿瘤产品中的应用。
应当说明的是，所述正辛酸除包括以下式Ⅰ所示结构的化合物实体，还包括正辛酸药学上可接受的盐、酯、溶剂化物、代谢产物或前药；所述式Ⅰ如下：
所述药学上可接受的盐，根据本领域通常的理解，通常表示正辛酸的碱金属盐，如钾盐、钠盐等。
优选的，所述预防和/或治疗肿瘤的产品为包括但不限于药物、保健品、特殊医用食品、模型药物中的一种。
优选的，所述肿瘤为包括但不限于皮肤癌，头颈癌，肺癌，食道癌，宫颈癌，子宫癌，膀胱癌，胰腺癌，乳腺癌，肾癌，输尿管癌，膀胱癌，肠道癌症，黑色素瘤，舌癌中的一种；进一步的方案中，所述肿瘤为腺癌；本发明证实的一种实施方式中，所述肿瘤为肺腺癌。
本发明第二方面，提供一种药物组合物，所述药物组合物中包括正辛酸。
本发明所述的“药物组合物”，或称“组合物”，其可用于在受试者特别是哺乳动物中实现治疗或预防本发明所述疾病。所述药物组合物优选的方案中，所述正辛酸作为活性成分，进一步的，为一种抗肿瘤活性成分。所述药物组合物中，正辛酸作为抗肿瘤活性成分，其应当是增效有效剂量的，所述药物剂量属于本领域技术可通过常规技术手段进行确定的技术内容。
本发明化合物的药物组合物，可以通过以下任意方式施与：口服、喷雾吸入、直肠给药、鼻腔给药、阴道给药、局部给药、非肠道给药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内或颅内注射或输入，或借助一种外植的储器用药，其中优选口服、肌注、腹膜内或静脉内用药方式。
具体的，所述药物组合物的剂型可以是液体剂型、固体剂型；液体剂型包括但不限于真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型；其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂、包合物、填埋剂、贴剂、擦剂等。
本发明的药物组合物中还可以含有常用的载体，这里所述可药用载体包括但不局限于：离子交换剂，氧化铝，硬脂酸铝，卵磷脂，血清蛋白如人血清蛋白，缓冲物质如磷酸盐，甘油，山梨酯，山梨酸钾，饱和植物脂肪酸的部分甘油酯混合物，水，盐或电解质，如硫酸鱼精蛋白，磷酸氢二钠，磷酸氢钾，氯化钠，锌盐，胶态氧化硅，三硅酸镁，聚乙烯吡咯烷酮，纤维素物质，聚乙二醇，羧甲基纤维素钠，聚丙烯酸酯，蜂蜡，羊毛酯等。载体在药物组合物中的含量可以是1 重量％-98重量％，通常大约占到80重量％。为方便起见，局部麻醉剂，防腐剂，缓冲剂等可直接溶于载体中。
本发明第三方面，提供一种抗肿瘤或抗炎药物，所述抗肿瘤药物中包括正辛酸，或第二方面所述药物组合物。
本发明以A549肿瘤细胞作为模型，证实了正辛酸能够直接抑制A549细胞的生长，抑制肿瘤细胞迁移、侵袭，从而实现压制肿瘤组织生长、转移的作用，并从机制通路的层面为上述抗肿瘤效果提供了相应的依据，启示了所述抗肿瘤药物可作为一种原位癌治疗药物或抑制肿瘤转移的药物。
另外，本发明研究还证实了，正辛酸能够显著降低肿瘤细胞中炎性因子的表达，这一方面启示了正辛酸可能通过改善炎症发展程度实现抗肿瘤作用，另一方面，还提供了正辛酸作为一种抗炎活性成分在抗炎药物中的应用。具体的实例中，所述炎症因子为IL-6、TNF-α。
除上述药物开发的技术方案，本发明还提供上述药物在疾病治疗及作为研究试剂中的使用方式。在作为模型药物的应用方式中，本发明第四方面，提供一种抑制炎性因子或肿瘤细胞增殖、迁移、侵袭的方法，所述方法包括有需要的个体施用正辛酸、第二方面所述药物组合物或第三方面所述药物。
应当明确的是，在上述第四方面所表示的技术方案中，所述“有需要的个体”表示本领域所使用的研究模型，包括但不限于表达载体、细胞模型、组织模型或动物模型等，其中，所述动物模型优选哺乳动物模型。
本发明第五方面，提供一种肿瘤治疗方法，所述治疗方法包括有需要的个体施予正辛酸、第二方面所述药物组合物获第三方面所述药物。
所述“施予”表示采用可确定剂量的方式给药，包括但不限于服用、注射或通过手术方式如介入治疗等进行给药。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。
图1为实施例1中所述正辛酸对A549细胞的抑制作用；
注：“**”与烟酰胺组相比，正辛酸组具有极显著性差异，P<0.01；
图2为实施例1中所述正辛酸对A549迁移的抑制作用；
图3为实施例1中所述正辛酸对A549侵袭的抑制作用；
图4为实施例1中所述细胞上清中IL-6因子的含量测定；
注：“**”与对照组相比，正辛酸组IL-6含量具有极显著性差异，P<0.01；
图5为实施例1中所述细胞上清中TNF-α因子的含量测定；
注：“**”与对照组相比，正辛酸组TNF-α含量具有极显著性差异，P<0.01；“*”与对照组相比，正辛酸组TNF-α含量具有显著性差异，P<0.05.
图6为实施例1中所述正辛酸对A549细胞蛋白的影响；
图7为实施例1中所述正辛酸对A549细胞IKK、TAK1、NF-κB p65和I κB表达的影响；
注：“**”与对照组相比，正辛酸组TNF-α含量具有极显著性差异，P<0.01；“*”与对照组相比，正辛酸组TNF-α含量具有显著性差异，P<0.05.
具体实施方式
应该指出，以下详细说明都是例示性的，旨在对本发明提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是，这里所使用的术语仅是为了描述具体实施方式，而非意图限制根据本发明的示例性实施方式。如在这里所使用的，除非上下文另外明确指出，否则单数形式也意图包括复数形式，此外，还应当理解的是，当在本说明书中使用术语“包含”和/或“包括”时，其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
为了解决如上的技术问题，本发明提供了正辛酸在制备预防和/或治疗肿瘤产品中的应用。
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案，以下将结合具体的实施例详细说明本发明的技术方案。
实施例1
郭健莲等人研究中，公开了烟酰胺具有体外抑制肺腺癌细胞GLC-82的增殖、迁移活性。本发明选用烟酰胺作为对照药物，对正辛酸的抗肺腺癌活性进行研究。
一、材料与方法
1.材料
药材：烟酰胺、正辛酸
细胞：人肺腺癌细胞A549
2.方法
2.1细胞培养
从超低温冰箱中取出A549细胞种子，于37℃水浴锅中快速融化。将融化好的冻存液在生物安全柜中轻轻吹打转移至2mL EP管中，1000r/min离心3 min，弃去上清液，然后向EP管中加入DMEM高糖培养基(含10％胎牛血清) 2mL，将细胞吹散转移至培养瓶中，补足培养基至5mL，放在37℃、5％CO2培养箱中培养，用于接下来的实验。
2.2药物对细胞的抑制作用
将生长对数期的A549细胞用胰蛋白酶消化吹打均匀，按照1×105的密度接种于96孔板，将板放置于37℃培养箱中进行培养孵育，待细胞密度长至90％后，吸去培养基，将烟酰胺、正辛酸分别从1mg/mL分别二倍稀释九个浓度，加至细胞中，设置细胞对照组，每个浓度分别重复四个复孔，继续培养24h，24 h后取出96孔板，弃去培养基，每孔加入稀释好的CCK8 100μL，将细胞培养板置于37℃黑暗环境培养2h后，用酶标仪测定450nm处每孔的吸光度OD 值，然后参照下面公式计算细胞存活率、抑制率。
细胞存活率＝[(给药组平均OD值－校准平均OD值)/(细胞对照组平均 OD值－校准平均OD值)]×100％
细胞抑制率＝1-细胞存活率
2.3划痕
将生长对数期的A549细胞用胰蛋白酶消化吹打均匀，按照1×106的密度接种于6孔板，将板放置于37℃培养箱中进行培养孵育，待细胞密度长至95％后，吸去培养基，用200μL黄色枪头垂直于6孔板底部划痕，划痕后用PBS洗细胞3次，去处划下的细胞，加入用无血清培养基稀释的烟酰胺、正辛酸，设置细胞对照组，每个浓度分别重复3个复孔，继续培养24h，24h后取出6孔板，弃去培养基，荧光倒置显微镜下观察拍照。
2.4 Transwell
将生长对数期的A549细胞用胰蛋白酶消化吹打均匀，按照1×106的密度接种于6孔板，将板放置于37℃培养箱中进行培养孵育，待细胞密度长至90％后，吸去培养基，加入用无血清培养基稀释的烟酰胺、正辛酸，设置细胞对照组，每个浓度分别重复3个复孔，继续培养24h。24h后，将基质胶与冷培养基1： 9的比例稀释，将Transwell小室放入24孔板内，每孔滴入25μL稀释好的基质胶，滴入后迅速震荡，使基质胶均匀的铺在小室底部，37℃孵育30min。将6 孔板中的细胞消化、计数后，每个小室中加入500μL无血清培养基，在下室加入600μL完全培养基(10％FBS)，将24孔板放入37℃培养箱培养，24h后将24孔板取出，小室放入500μL的4％组织固定液中固定20min，吸出组织固定液后，加入500μL的0.1％结晶紫染色30min，擦去基质胶，洗去多余结晶紫及背景色，将上室、24孔板倒置晾干，拍照。
2.5 ELISA法
将生长对数期的A549细胞用胰蛋白酶消化吹打均匀，按照1×105的密度接种于96孔板，将板放置于37℃培养箱中进行培养孵育，待细胞密度长至90％后，吸去培养基，将烟酰胺、正辛酸分别从1mg/mL分别二倍稀释，加至细胞中，设置细胞对照组，每个浓度分别重复四个复孔，继续培养24h，24h后取出 96孔板，取上清，根据ELISA试剂盒说明书测定上清中IL-6和TNF-α因子的含量。
2.6 Western Blot
将A549细胞按照1×106的密度接种于6孔板培养，待细胞密度长至90％后，吸去培养基，加入用无血清培养基稀释的烟酰胺、正辛酸，设置细胞对照组，每个浓度分别重复3个复孔，继续培养24h。24h后，用预冷的PBS洗两遍，消化离心，收集细胞，加入预先配好的IP裂解液，冰上裂解30min，离心取上清得到蛋白样品。采用BCA法进行蛋白定量，绘制标准曲线，根据曲线计算待测样品的蛋白浓度，用5×上样缓冲液和细胞裂解液稀释，将待测样品蛋白浓度调整为25μg/μL。然后100℃加热5min，冷却后混匀，变性后的蛋白样品于-80℃保存。取各组样品蛋白10μg上样，经SDS-PAGE电泳分离后，转移至PVDF 膜上，封闭液封闭1h，TBST洗涤3次，一抗TAK1、NF-κB p65、IKK、IκB 和GADPH 4℃孵育过夜后，TBST洗涤3次，HRP标记二抗室温摇床1h， TBST洗涤后ECL发光，显影，定影，通过Image J软件分析目的蛋白相对灰度值的差异。
二、结果
1.药物对A549细胞的抑制作用
烟酰胺和正辛酸不同浓度对A549细胞均有一定的抑制作用。从表1和图1 可以看出，正辛酸的抑制作用明显大于烟酰胺，正辛酸的IC50为20.66，烟酰胺的IC50为190.74。
表1.烟酰胺和正辛酸对A549细胞的抑制作用
2.划痕实验
从图中可以看出，与阴性对照组相比，给药24h后，正辛酸能抑制A549细胞的迁移。
3.Transwell实验
烟酰胺和正辛酸均能抑制A549细胞的迁移。从图中可以看出，与阴性对照组相比，给药24h后，正辛酸组细胞数量明显减少。
4.ELISA
从图表中可以看出，正辛酸组细胞上清液中IL-6(表2)和TNF-α(表3) 的含量均显著低于阴性对照组，表明正辛酸能够通过降低炎症反应来实现抗肿瘤的效果。
表2.细胞上清中IL-6因子的含量测定
表3.细胞上清中TNF-α因子的含量测定
5.Western Blot
Western Blot分析结果如图6所示，与阴性对照组相比，正辛酸组可显著降低细胞中IKK、TAK1、NF-κB p65和IκB的表达，表明正辛酸能通过抑制 TAK1/NF-κB通路从而抑制肿瘤细胞的侵袭迁移。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (1)
1.正辛酸在制备治疗肿瘤产品中的应用，其中，所述肿瘤为肺腺癌。
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