CN106822904B - 含akt抑制剂和ire1抑制剂的药物组合物及其应用 - Google Patents
含akt抑制剂和ire1抑制剂的药物组合物及其应用 Download PDFInfo
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Abstract
本发明涉及一种含AKT抑制剂和IRE1抑制剂的药物组合物及其在制备防治肿瘤药物中的应用，所述的AKT抑制剂选自MK‑2206、Perifosine、Ipatasertib或AZD5363，优选为MK‑2206；所述的IRE1抑制剂选自STF‑083010、APY29或4μ8C，优选为STF‑083010。所述的药物组合物以MK‑2206和STF‑083010联合用药，为肿瘤患者提供一种新的治疗方案，可有效抑制肿瘤细胞的生长和细胞克隆形成，效果显著优于单独用药，具有相加或协同效应，同时对正常细胞的毒副作用低，安全性高，可应用于制备抗肿瘤的药物领域。
Description
技术领域
本发明属于医药技术领域，具体涉及一种含AKT抑制剂和IRE1抑制剂的药物组合物及其应用。
背景技术
癌症是仅次于心血管疾病的高死亡率疾病，全球癌症患者和死亡病例都在不断地增加。新增癌症病例有近一半出现在亚洲，其中大部分在中国，中国新增癌症病例高居世界第一位。尤其是在肝癌、食管癌、胃癌和肺癌等4种恶性肿瘤中，中国新增病例和死亡人数均居世界首位。这些癌症的治疗虽然以手术为主，但由于早期患者一般无明显症状，在首次被确诊的癌症患者中，很多已为中晚期，失去了手术切除的机会，故非手术治疗在肿瘤的综合治疗中有着十分重要的地位。其中，化疗无论是术前化疗、术后辅助化疗还是姑息性化疗，在综合治疗中占据举足轻重的地位。目前常用的化疗药物多以长春瑞滨、紫杉醇、氟尿嘧啶、顺铂、5-氟尿嘧啶为主，其产生的化疗反应，如恶心呕吐较强烈以及对肝肾功能和骨髓损害等，一定程度上限制了其应用。
AKT信号传导通路是细胞内重要的信号传导通路之一，它参与调节肿瘤细胞的增殖、存活、迁移、黏附、肿瘤血管生成等过程，并在多种常见肿瘤(如乳腺癌、肺癌、胃癌、前列腺癌、宫颈癌和血液系统肿瘤)中均有高表达。因此，以AKT为靶点的分子靶向治疗也逐渐得到人们的重视。其中，MK-2206是一种高度选择性的AKT1/2/3抑制剂，其主要作用是抑制AKT磷酸化，对250种其他蛋白激酶没有抑制活性，目前已进入Ⅱ期临床试验研究。Perifosine(KRX-0401)是一种新型的AKT抑制剂，为一杂环的烷基磷酸胆碱，可靶向作用于Akt的pleckstrin同源结构域来抑制AKT的活性，表现出良好的抑制乳腺癌在内的多种实体瘤活性，目前已进入Ⅲ期临床试验研究。Ipatasertib(GDC-0068)是一种高选择性的广谱AKT抑制剂，靶向作用于AKT1/2/3，比作用于PKA选择性高620倍，目前已进入Ⅱ期临床试验研究。AZD5363作为AKT抑制剂，可有效抑制AKT(AKT1/2/3)的所有亚型，对P70S6K/PKA也具有相似的抑制效果，而对ROCK1/2抑制活性较低，目前已进入Ⅱ期临床试验研究。
肌醇需求激酶1(IRE1)是一种定位于内质网膜的跨膜蛋白，参于未折叠蛋白反应(UPR)信号通路中信息的传递。其中，IRE1α/Xbp1通路是UPR的重要传感通路，IRE1α通过感知内质网压力，使激酶区域自磷酸化进而激活核酸酶活性，在mRNA水平上剪切其下游转录因子Xbp1，激活一系列的UPR相关基因的转录，从而缓解内质网压力，还可通过非依赖Xbp1的途径，激活JNK，引发细胞的凋亡。STF-083010是一种特异性IRE1核酸内切酶抑制剂，具有剂量和时间依赖性的细胞抑制能力和细胞毒性，STF-083010可抑制XBP1剪接，抑制IRE1α的核酸内切酶活性，但不影响IRE1α的激酶活性。APY29是IRE1变构调节剂，能抑制IRE1R自磷酸化，并激活IRE1RNase活性。而4μ8C是高效的选择性IRE1抑制剂，它可阻断基底(RIDD)接近IRE1的活性部位，并选择性使Xbp1剪接作用和IRE1介导的mRNA降解失活。目前，关于IRE1α/Xbp1通路的研究多与脂肪代谢调控有关，很少涉及到肿瘤的防治。
随着肿瘤分子生物学的研究进展，肿瘤分子靶向治疗已成为肿瘤研究的热点，在多种肿瘤的治疗中发挥了重要的作用。然而，大部分肿瘤的生物学行为并非由单一信号传导通路所支配，而是多个信号传导通路共同起作用的，因此联合用药针对多靶点进行靶向治疗将不仅旨在减少或延缓耐药性的出现、降低毒性，而且通过多种药物对癌细胞杀伤的协同作用取得更好的疗效。目前，没有关于AKT抑制剂和IRE1抑制剂联合用药用于抗肿瘤的相关研究报道。
发明内容
为解决现有技术存在的问题，本发明的目的在于提供一种药物组合物及其在制备防治肿瘤的药物中的应用，具体涉及含有AKT抑制剂和IRE1抑制剂的药物组合物及其在制备治疗肺癌、肝癌、食管癌、肠癌、胃癌、脑瘤、胰腺癌、卵巢癌、乳腺癌或前列腺癌的药物中的应用。
本发明提供一种药物组合物，其包含有AKT抑制剂和IRE1抑制剂。
其中，所述的AKT抑制剂选自MK-2206、Perifosine(KRX-0401)、Ipatasertib(GDC-0068)或AZD5363。
所述的IRE1抑制剂选自STF-083010、APY29或4μ8C。
优选地，所述的AKT抑制剂为MK-2206。
优选地，所述的IRE1抑制剂为STF-083010。
优选地，所述的药物组合物包含有MK-2206和STF-083010。
进一步地，所述的药物组合物中MK-2206和STF-083010的摩尔浓度比为1～20:10～60。
优选地，所述的药物组合物中MK-2206和STF-083010的摩尔浓度比为5:40。
此外，本发明还请求保护上述的药物组合物在制备防治肿瘤药物中的应用，所述的肿瘤包括但不限于肺癌、肝癌、食管癌、肠癌、胃癌、脑瘤、胰腺癌、卵巢癌、乳腺癌或前列腺癌。
优选地，本发明请求保护上述的药物组合物在制备防治肺癌、肝癌、食管癌药物中的应用。
进一步地，所述的药物组合物可配以药学可接受的添加剂制成注射制剂或口服制剂，优选注射制剂，尤其是静脉注射制剂。
磷脂酰肌醇-3-激酶(PI3K)及蛋白激酶B(AKT)所组成的信号通路与肿瘤增殖、凋亡、转移、侵袭及血管生成密切相关。作为该通路的核心，异常活化的AKT通过磷酸化其下游分子(如mTOR)促进肿瘤恶性增殖及抵抗凋亡，并参与调节肿瘤对放化疗及靶向治疗的敏感性。特异性抑制AKT分子活化能有效阻断PI3K/AKT信号通路，抑制肿瘤增殖，促进凋亡。本发明人以MK-2206单独处理食管癌细胞株Kyse450、Kyse510、TE-1、Eca-109、EC9706，发现MK-2206对食管癌细胞的生长具有一定的抑制作用，使癌症细胞数明显减少，并且发现MK-2206通过抑制AKT及mTOR的磷酸化，使p-AKT和p-mTOR的表达显著下调，从而有效阻断PI3K/AKT/mTOR信号通路，充分发挥抑制肿瘤增殖，促进凋亡效果。
一方面，本发明人以MK-2206和STF-083010联合用药，观察其对食管癌、肺癌、肝癌细胞和正常血管内皮细胞的影响，结果发现，MK-2206和STF-083010联合用药，可显著抑制癌细胞的存活，减少癌细胞的数量，效果显著优于单独使用MK-2206或STF-083010，对食管癌、肺癌、肝癌细胞的抑制效果均显示出较佳的协同作用，同时，联合用药对正常血管内皮细胞的毒性较小。
另一方面，本发明人还考察了MK-2206和STF-083010联合用药对食管癌细胞克隆形成的影响，结果显示，与对照组以及单药组相比，联合用药对细胞克隆形成具有明显的协同抑制作用，联合用药组细胞克隆数量最少，同时体积也最小，表明MK-2206和STF-083010联合用药联合用药对抑制食管癌细胞克隆具有较佳的协同作用。
与现有技术相比，本发明的优势在于：
本发明提供一种用于防治肿瘤的药物组合物，具体为将AKT抑制剂和IRE1抑制剂组合使用，更具体为以MK-2206和STF-083010联合用药，为肿瘤患者提供一种新的治疗方案，所述的MK-2206和STF-083010联合用药，可有效抑制肿瘤细胞的生长和细胞克隆形成，效果显著优于单独用药，具有相加或协同效应，同时对正常细胞的毒副作用低，安全性高，可应用于制备抗肿瘤的药物领域。
附图说明
图1MK-2206单独使用对食管癌细胞生长的影响。
图2MK-2206单独使用对食管癌细胞形态的影响。
图3MK-2206单独使用对食管癌细胞mTOR/AKT通路的影响。
图4MK-2206与STF-083010联合作用对食管癌细胞生长的影响。
图5MK-2206与STF-083010联合作用对食管癌细胞形态的影响。
图6MK-2206与STF-083010联合作用对食管癌细胞的联用效果分析。
图7MK-2206、顺铂、5-氟尿嘧啶与STF-083010联合作用对肿瘤细胞及正常细胞的影响。
图8MK-2206与STF-083010联合作用对食管癌细胞克隆形成的影响。
具体实施方式
以下通过具体实施方式进一步描述本发明，但本发明不仅仅限于以下实施例。
实施例1MK-2206单独处理后对食管癌细胞生长的影响
首先检测Kyse450、Kyse510、TE-1、Eca-109、EC9706食管癌细胞对MK-2206单独使用的药物敏感性。
1、实验方法
将肿瘤细胞以每孔4000-6000个细胞的数量接种到96孔板，待细胞贴壁(24h)后，将MK-2206药物稀释成一定的梯度浓度，每浓度设5复孔，分为实验组及调零组加药。48h后采用MTT法进行细胞活力检测，每孔加入10μl MTT溶液，继续培养4h，小心吸除孔内液体，避免接触孔内结晶物，每孔加入100μl的DMSO，于恒速摇床上避光摇晃。待结晶物充分溶解后，在酶标仪上读取OD值(波长570nm，参考波长630nm)，测得吸光度A值。
生长抑制率的计算公式为：生长抑制率(％)＝(1-OD实验组/OD对照组)×100％。根据各浓度的抑制率可作图得到剂量反应曲线，作图软件为Graphpad，采用Logit法精确计算药物的IC50(half maximal inhibitory concentration)值。具体结果见图1和图2。
从图1可以看出，MK-2206对食管癌细胞株Kyse450、Kyse510、TE-1、Eca-109、EC9706的IC50值分别为14.3、12.4、9.4、7.6和11.5，表明MK-2206对食管癌细胞的生长具有一定的抑制作用。从图2也可以看出，MK-2206单独作用于食管癌细胞株Kyse450、Kyse510后，细胞数明显减少。
实施例2MK-2206单独使用对食管癌细胞mTOR/AKT通路的影响
利用Western blot方法检测经MK-2206单独处理及联合处理后食管癌细胞Kyse450和Kyse510细胞内mTOR/AKT通路相关蛋白的表达情况。先将Kyse450和Kyse510细胞分别以每孔2×105个细胞的密度接种至6孔板。待细胞贴壁后，按实施例1给药。处理48h后，分别收取各组细胞全蛋白。先经SDS电泳后，将蛋白转移至PVDF膜上，5％脱脂奶粉室温封闭1h，孵育所需检测的蛋白相对应的一抗，4℃孵育过夜。24h回收一抗，用TBST清洗3次，每次5min，之后孵育二抗，室温孵育1h。后用TBST清洗3次，每次5min，之后ECL显影，结果见图3。
从图3可以看出，在Kyse450和Kyse510细胞中，当用MK-2206单独处理后，p-AKT和p-mTOR的表达显著下调，说明MK-2206能够抑制AKT及mTOR的磷酸化，使p-AKT和p-mTOR的表达显著下调，从而有效阻断PI3K/AKT/mTOR信号通路，充分发挥抑制肿瘤增殖，促进凋亡效果。
实施例3MK-2206与STF-083010联合作用对食管癌细胞生长的影响
将人食管癌细胞Kyse450和Kyse510细胞以每孔4000-6000个细胞的数量接种到96孔板，待细胞贴壁后，加入5μM浓度MK-2206和40μM浓度STF-083010，培养48h后，每孔加入10μl浓度为5mg/ml的MTT溶液，继续培养4h，然后弃去培养液每孔加入100μl的DMSO，于恒速摇床上避光摇晃。待结晶物充分溶解后，在酶标仪上读取OD值(波长570nm，参考波长630nm)，读取每孔的吸光值，计算两药合用后细胞存活率。用CompuSyn软件进行协同作用综合因子(Combination Index,CI)分析，结果见图4。并通过显微镜观察5μM浓度MK-2206和40μM浓度STF-083010联合作用于食管癌细胞细胞形态变化，结果如图5。
如图4所示，5μM浓度MK-2206和40μM浓度STF-083010联合使用具有很好的联用效果。从图5可知，MK-2206与STF-083010两药联用后癌细胞数明显减少，细胞形态较正常组及单独用药组相比无明显变化。
CI值表示药物联合作用时的一个复合指数，CI值小于1、等于和大于1分别表示药物协同作用、增效作用和拮抗作用。从图6可以看出，MK-2206和STF-083010对食管癌细胞联合使用时，其CI值基本都在小于1的范围内，特别是Kyse450，表明MK-2206和STF-083010在本发明的用量范围内联合使用具有很好的协同作用。
实施例4MK-2206、顺铂、5-氟尿嘧啶和STF-083010联合作用对肿瘤细胞及正常细胞的影响
将Kyse450食管癌、Kyse510食管癌、A549肺癌、HepG2肝癌细胞和HUVEC正常血管内皮细胞以每孔3000-6000个细胞的数量接种到96孔板，待细胞贴壁后，加入对照组、5μM的MK-2206和40μM的STF-083010及联合用药组药物；另铺细胞Kyse450，按照如下方式进行加药：对照组、5μM MK-2206、40μM STF-083010、MK-2206+STF-083010、1μg/ml顺铂(CDDP)、顺铂(CDDP)+STF-083010、4μg/ml 5-氟尿嘧啶(5-FU)、5-氟尿嘧啶(5-FU)+STF-083010，培养48h后，每孔加入10μl浓度为5mg/ml的MTT溶液，继续培养4h，然后弃去培养液每孔加入100μl的DMSO，于恒速摇床上避光摇晃。待结晶物充分溶解后，在酶标仪上读取OD值(波长570nm，参考波长630nm)，读取每孔的吸光值，计算两药合用后的细胞存活及抑制率，结果见图7。
如图7所示，YM155和STF-083010在肿瘤细胞中组合使用具有很好的联合效果，且优于顺铂、5-氟尿嘧啶与STF-083010组合，而对正常HUVEC细胞的毒性较小。
实施例5MK-2206和STF-083010联合用药对食管癌细胞克隆形成的影响
将人食管癌细胞Kyse450和Kyse510细胞接种到6孔板，待细胞贴壁过夜后，将细胞分为对照组、MK-2206单药组、STF-083010单药组及MK-2206和STF-083010药物联合用药组，分别加入对应的培养基或者药物溶液，孵育7天，检测细胞平板克隆形成情况。结果如图8所示，与对照组以及单药组相比，联合用药对细胞克隆形成具有明显的协同抑制作用，联合用药组细胞克隆数量最少，同时体积也最小。
以上仅是本发明的优选实施方式，应当指出的是，上述优选实施方式不应视为对本发明的限制，本发明的保护范围应当以权利要求所限定的范围为准。对于本技术领域的普通技术人员来说，在不脱离本发明的精神和范围内，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (3)
1.一种药物组合物，其特征在于，所述的药物组合物包含有AKT抑制剂和IRE1抑制剂；所述的AKT抑制剂为MK-2206，所述IRE1抑制剂为STF-083010；所述的药物组合物中MK-2206和STF-083010的摩尔浓度比为1～20:10～60。
2.根据权利要求1所述的药物组合物，其特征在于，所述的药物组合物中MK-2206和STF-083010的摩尔浓度比为5:40。
3.如权利要求1或2所述的药物组合物在制备治疗食管癌药物中的用途。
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