CN105833173B - 冬凌草甲素联合姜黄素在制备白血病治疗药物中的应用 - Google Patents
冬凌草甲素联合姜黄素在制备白血病治疗药物中的应用 Download PDFInfo
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- CN105833173B CN105833173B CN201610238624.6A CN201610238624A CN105833173B CN 105833173 B CN105833173 B CN 105833173B CN 201610238624 A CN201610238624 A CN 201610238624A CN 105833173 B CN105833173 B CN 105833173B
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Abstract
本发明公开了冬凌草甲素联合姜黄素在制备白血病治疗药物中的应用。本发明研究发现,将不同抗癌机理的中草药有效成分冬凌草甲素与姜黄素进行定量配伍的联合用药,会产生显著的协同增效效果。上述配伍方式能够以较低浓度的药物组合杀伤更多的白血病细胞,并能有效减低药物对白血病细胞增殖抑制率达50%时所对应的药物总浓度,而且此种配伍方式中各药物的使用量均不属于能够对机体造成伤害的范围。因此,本发明中冬凌草甲素与姜黄素的联合用药方案不论是在制备白血病治疗药物还是在白血病的防治和研究方面,都具有重要的意义和广泛的应用前景。
Description
技术领域
本发明属于生物医药技术领域。更具体地,涉及冬凌草甲素联合姜黄素在制备白血病治疗药物中的应用。
背景技术
白血病俗称“血癌”,是一类来源于造血干细胞的恶性血液肿瘤疾病。当前,对白血病的治疗主要集中于以下方案:化疗、放疗、骨髓移植和免疫疗法等等。其中,化疗因其靶向性相对较强、治疗费用相对低廉而成为白血病治疗中的主流方案。
在常用的化疗方案里,联合用药的思路得到了充分的体现。目前临床常用的联合用药方式中多以西药联合西药、西药联合中药为主,且所用西药大多为细胞周期的特异性或非特异性阻滞药物,利用白血病细胞的异常增殖特性对该病进行治疗。
然而,上述疗法在应用中也存在很大的问题:首先,以细胞周期阻滞药为主的化疗方案虽然阻止了白血病细胞的异常增殖,但也阻碍了正常机体细胞的分裂;第二,西药代谢过程复杂,对患者的心、肝、肾等重要器官损伤严重;第三,靶向化疗药物价格不菲,普通人家较难长期承受。
发明内容
本发明要解决的技术问题是克服现有治疗白血病药物的缺陷和不足,主要是化疗方案的靶向性差(即不区分正常细胞与癌变细胞,强制性阻滞机体所有细胞的增殖)、副作用强、成本高昂等弊端,提供一种将两种不同抗癌机理的中草药有效成分——冬凌草甲素(Oridonin,简称Ori)和姜黄素(Curcumin,简称Cur)进行配伍的联合用药方法,既可以利用两种化合物间显著的协同增效效果来达到低剂量高效率的杀死白血病细胞的目的。同时由于中草药低毒且来源丰富、材料易得,能够大大减少治疗过程中药物对机体的毒副作用并显著降低治疗成本。
本发明的目的是提供冬凌草甲素与姜黄素配伍的联合用药方案在制备白血病治疗药物中的应用。
本发明另一目的是提供一种白血病治疗药物。
本发明上述目的通过以下技术方案实现:
冬凌草联合姜黄在制备白血病预防、治疗、辅助治疗和/或预后防复发的药物中的应用。
冬凌草甲素联合姜黄素在制备白血病预防、治疗、辅助治疗和/或预后防复发的药物中的应用。
具体是冬凌草甲素联合姜黄素按一定比例配伍而成的高效低毒的药物组合物在制备白血病预防、治疗、辅助治疗和/或预后防复发的药物中的应用。
所述冬凌草甲素或姜黄素包括其可药用的盐和酯、选择性取代的类似物或者一种或多种前述化合物的组合;还包括二者的衍生物,或者二者及其衍生物在药学上可接受的盐或盐的溶剂化物。
上述的药物具有高效低毒的优点。
在上述的联合配伍方案中起减毒增效的活性成分为冬凌草甲素和姜黄素。
优选地,在上述应用方案中,冬凌草甲素和姜黄素的摩尔浓度比为0.1~15:0.1~30。
优选地,冬凌草甲素和姜黄素的摩尔浓度比为10:5或5:20。
优选地,冬凌草甲素和姜黄素联用的浓度分别为:冬凌草甲素配伍的浓度小于15µM,姜黄素配伍的浓度小于30µM。
更优选地,冬凌草甲素配伍的浓度小于10µM,姜黄素配伍的浓度小于20µM。
最优选地:10µM的冬凌草甲素配伍5µM的姜黄素,或5µM的冬凌草甲素配伍20µM的姜黄素。
当冬凌草甲素10µM配伍姜黄素5µM或者冬凌草甲素5µM配伍姜黄素20µM时,药物组合物对白血病细胞的增殖抑制率即可达50%;而且该两种配伍方式的使用量均不属于能够对机体造成伤害的范围。
一种治疗白血病的药物组合物,包含有效量的冬凌草和姜黄,或包含有效量的冬凌草甲素和姜黄素。
进一步地,上述药物组合物还可以包括可接受的药用载体制成各种药学上可接受的制剂,包括针或冻干粉针制剂、丸剂、汤剂、片剂、颗粒剂、硬胶囊、软胶囊、控释、缓释制剂、注射剂或口服制剂。
所述药用载体包括(但并不限于):盐水、缓冲液、葡萄糖、水、甘油、乙醇、低分子量右旋糖酐、聚乙二醇400、 聚乙二醇6000、甘露醇、乳糖、葡萄糖、蔗糖、氯化钠以及山梨醇中的一种或几种的组合。
本发明的冬凌草甲素和姜黄素组成的药物的制备方法不做严格限制,如可以被制成针剂形式,例如用生理盐水或含有葡萄糖和其他辅剂的水溶液通过常规方法进行制备。诸如片剂和胶囊之类的药物组合物,可通过常规方法进行制备。药物组合物如针剂、溶液、片剂和胶囊宜在无菌条件下制造。
更进一步地,上述的药物组合物还可以包括一种以上的药学上可接受的赋形剂。
另外,上述的药物组合物还可包括其他化疗药物、抗炎类药物、激素类药物、小分子靶向药物、抗体药物、中药复方制剂及中药提取物和/或中药单体及其衍生物,从而制备成不同针对性的药物。
具体优选地,所述其他化疗药物或抗癌试剂可以为(但不限于)以下的一种或多种:足叶乙苷、5-氟尿嘧啶、环磷酰胺、阿霉素、柔红霉素、表柔比星、阿糖胞苷、靛红、顺铂、卡铂、依托泊苷、拓扑替康、伊立替康等等。
所述抗炎类药物或免疫刺激剂可以为(但不限于)以下的一种或多种:阿司匹林、干扰素、c-AMP、球蛋白等等。
所述激素类药物可以为(但不限于)以下的一种或多种:糖皮质激素、雌激素、孕激素等等。
所述小分子靶向药物可以为(但不限于)以下的一种或多种:伊马替尼(Imatinib)、达沙替尼(Dasatinib)、尼罗替尼(Nilotinib)、伯舒替尼(Bosutinib)、舒尼替尼(Sutent, Sunitinib)、索拉非尼(Nexavar, Sorafenib)、拉帕替尼(Lapatinib)、易瑞沙(Gefitinib)等等。
所述抗体类药物可以为(但不限于)以下的一种或多种:美罗华(Rituximab,Rituxan)、贺赛汀(Trastuzumab,Herceptin)、爱必妥(Cetuximab, Erbitux)、贝伐单抗(Bevacizumab,Avastin)、帕尼单抗(Panitumumab)、尼妥珠单抗(Nimotuzumab)等等。
所述抗肿瘤中药复方制剂及中药提取物可以为以(但不限于)下的一种或多种:灵芝提取物、云芝提取物、茯苓提取物、薏苡仁提取物、枫苓合剂、蟾酥灵等等。
所述中药单体及其衍生物可以为(但不限于)以下的一种或多种:紫杉醇、喜树碱、高三尖杉酯碱、青蒿素、大豆异黄酮、人参皂苷、长春新碱、秋水仙碱、柚皮素、大黄素及其衍生物、苦参碱及其衍生物、雷公藤甲素及其衍生物等等。
另外,上述药物组合物在制备减毒增效抗白血病的药物、预防白血病的药物、提高机体免疫力的药物、保健药品或保健食品方面的应用,以及由此制备得到的所述药物,也在本发明的保护范围之内。
本发明提出了将具有不同抗癌机理的中草药有效成分冬凌草甲素与姜黄素进行配伍的联合用药方式,并给出了具体的配伍剂量和相应剂量下细胞增殖的抑制情况,该配伍方式能够大大提高药物对白血病细胞的增殖抑制效果,使药物对白血病细胞的增殖抑制率达50%时所对应的药物总浓度显著下降。
本发明还确定了该药物组合物(冬凌草甲素与姜黄素配伍)在一定剂量配伍条件下具有明显的协同增效效果,这使它们可以以相对低的剂量应用于白血病的临床治疗、辅助治疗以及预后防复发的相关治疗,该配伍组合既提高了药物的总疗效也减少了副作用的发生。本发明公开了含有所述化合物的药物组合物及其相关配比和所述药物组合物在高效低毒地防治白血病方面的应用。
本发明具有以下有益效果:
本发明具体涉及联用不同抗癌机理的中草药有效成分对白血病进行高效低毒的治疗,主要是将中草药冬凌草和姜黄中的有效成分冬凌草甲素与姜黄素进行定量配伍的联合用药,产生协同增效的效果。
上述配伍方式(冬凌草甲素与姜黄素)中,冬凌草甲素与姜黄素的联合使用能够起到很好的协同增效作用,该药物组合能够显著减少使白血病细胞达到半数增殖抑制率时所对应的药物总浓度(即能有效减低药物对白血病细胞增殖抑制率达50%时所对应的药物总浓度),而且此两种配伍方式的使用量均不属于能够对机体造成伤害的范围。
因此,本发明的冬凌草甲素联合姜黄素联合药物方案在制备白血病治疗药物和白血病的防治和研究方面,都具有重要的意义和广泛的应用前景。
附图说明
图1为5uM冬凌草甲素联用不同浓度姜黄素的药物配伍方式对慢性随性白血病细胞株K562细胞的增殖抑制情况。
图2为10uM冬凌草甲素联用不同浓度姜黄素的药物配伍方式对慢性随性白血病细胞株K562细胞的增殖抑制情况。
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明,以下实施例所用试剂和材料均为市购。
实施例1 冬凌草甲素与姜黄素联合用药研究
选用一定浓度梯度的冬凌草甲素与姜黄素分别处理白血病K562细胞24小时,同时固定抗癌药物冬凌草甲素的浓度、联合使用不同梯度浓度的姜黄素处理白血病K562细胞24小时,用MTT比色法计算细胞在三种不同的药物处理模式下各自的增殖抑制强度。具体研究方法如下:
1、实验细胞株
K562慢性髓性白血病细胞取自中山大学生物工程研究中心(广东,广州)。
2、细胞培养:
K562细胞用完全培养基(含10% FBS和1% 双抗的RPMI-1640培养基)进行常规细胞培养,培养时采用37℃恒温、5% CO2的条件进行。
3、药物母液配制实验:
取购自河南济世制药有限公司的冬凌草甲素粉末和购自Sigma公司的姜黄素粉末,称重,并用DMSO溶液溶解,至终浓度为40mM。
4、细胞增殖抑制实验:
(1)获取细胞
取培养至对数生长期的白血病K562细胞,750rpm离心3分钟进行收集,用含10%胎牛血清的RPIM 1640培养基重悬细胞,并将细胞悬液的浓度调至3×105个/ml,以98µL/孔的量将上述细胞悬液接入96孔板内,置于37℃, 5% CO2培养箱中培养24小时;
(2)加药处理
A. 取配好的40mM冬凌草甲素母液用DMSO溶液稀释至工作浓度(5µM和10µM)的100倍,故配制浓度分别为0.5mM和1mM,吹打混匀;
B. 取配好的40 mM姜黄素母液用DMSO溶液稀释至工作浓度(5µM,10µM, 20µM和30µM)的100倍,故配制浓度分别为0.5mM,1mM,2mM和3mM,吹打混匀;
C. 在(1)中96孔板内的每孔细胞悬液中加入稀释好的药物,分为姜黄素单独用药组、5µM冬凌草甲素与姜黄素联合用药组、10µM冬凌草甲素与姜黄素联合用药组:
姜黄素单独用药组:每孔加入1µL B中稀释好的各浓度姜黄素溶液和1µL DMSO溶液,姜黄素0µM对照孔为仅加入2µL DMSO溶液,晃动培养板以混匀,置于37℃, 5% CO2培养箱中培养24小时;
5µM冬凌草甲素与姜黄素联合用药组:每孔加入1µL A中稀释好的0.5mM冬凌草甲素溶液和1µL B中稀释好的各浓度姜黄素溶液,冬凌草甲素5µM姜黄素0µM对照孔为加入1µLA中稀释好的0.5 mM冬凌草甲素溶液和1µL DMSO溶液,晃动培养板以混匀,置于37℃, 5%CO2培养箱中培养24小时;
10µM冬凌草甲素与姜黄素联合用药组:每孔加入1 µL A中稀释好的1 mM冬凌草甲素溶液和1µL B中稀释好的各浓度姜黄素溶液,冬凌草甲素10µM姜黄素0µM对照孔为加入1µL A中稀释好的1 mM冬凌草甲素溶液和1µL DMSO溶液,晃动培养板以混匀,置于37℃,5%CO2培养箱中培养24小时;
(3)在各孔细胞悬液内加入15µL MTT溶液(MTT试剂盒购自Promega公司,USA),置于37℃,5% CO2培养箱中培养4小时;
(4)在(3)中各孔内加入100µL STOP溶液,置于37℃,5% CO2培养箱中培养24小时;
(5)取出96孔培养板,分别于570nm波长和630nm波长的激发光下检测各孔的吸光值,A570-A630,即为各孔真实的吸光值,反应的是各孔中细胞的存活率,据此可算出各孔细胞在药物作用下的增殖抑制情况。
5、实验结果
结果如附图1和2所示,冬凌草甲素与姜黄素的联合使用能够起到很好的协同增效作用。
该药物组合能够显著减少使白血病细胞达到半数增殖抑制率时所对应的药物总浓度:冬凌草甲素5µM配伍姜黄素20µM(如图1所示)或者冬凌草甲素10µM配伍姜黄素5µM(如图2)即可,此两种配伍方式的使用量均不属于能够对机体造成伤害的范围。
Claims (5)
1.冬凌草甲素联合姜黄素在制备白血病预防、治疗、辅助治疗和/或预后防复发的药物中的应用,其特征在于,所述冬凌草甲素包括冬凌草甲素,以及其可药用的盐或酯;所述姜黄素包括姜黄素,以及其可药用的盐或酯;其中,冬凌草甲素和姜黄素的摩尔浓度比为10:5或5:20。
2.一种治疗白血病的药物组合物,其特征在于,包含有效量的冬凌草甲素和姜黄素,所述冬凌草甲素包括冬凌草甲素,以及其可药用的盐或酯;所述姜黄素包括姜黄素,以及其可药用的盐或酯;其中,冬凌草甲素和姜黄素的摩尔浓度比为10:5或5:20。
3.根据权利要求2所述的药物组合物,其特征在于,所述药物可口服给药,还包括可接受的药用载体制成各种药学上可接受的制剂,包括针或冻干粉针制剂、丸剂、汤剂、片剂、颗粒剂、硬胶囊、软胶囊、控释或缓释制剂。
4.根据权利要求2所述的药物组合物,其特征在于,还包括一种以上的药学上可接受的赋形剂。
5.权利要求2所述的药物组合物在制备减毒增效抗白血病的药物、预防白血病的药物、提高机体免疫力的药物或保健药品方面的应用。
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