CN108484633A - 一种增强砷剂治疗白血病的单体化合物 - Google Patents
一种增强砷剂治疗白血病的单体化合物 Download PDFInfo
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Abstract
本发明涉及一种增强砷剂治疗白血病的单体化合物,包括:青蒿素、双氢青蒿素、青蒿琥酯、蒿甲醚以及其他青蒿素类衍生物,其中青蒿素类衍生物本身有抗白血病的作用,可以增强三氧化二砷治疗白血病的疗效,青蒿素类衍生物、砷剂和维甲酸三者联用抗白血病效果最好,可以通过抑制肿瘤细胞增殖和诱导肿瘤细胞分化和凋亡、调控细胞信号转导、抑制肿瘤血管新生、抑制肿瘤侵袭转移、增敏抗肿瘤化疗药物及逆转耐药等多种机制发挥抗肿瘤作用,以实现通过体内动物实验和体外细胞实验证实青蒿素类衍生物联合砷剂对治疗白血病有确切疗效。
Description
技术领域
本发明属于中药技术领域,具体涉及一种增强砷剂治疗白血病的单体化合物。
背景技术
白血病(leukemia)是一类造血干细胞恶性克隆性疾病。克隆性白血病细胞因为增殖失控、分化障碍、凋亡受阻等机制在骨髓和其他造血组织中大量增殖累积,并浸润其他非造血组织和器官,同时抑制正常造血功能。临床可见不同程度的贫血、出血、感染发热以及肝、脾、***肿大和骨骼疼痛。目前白血病的病因尚未完全阐明。较为公认的因素有:病毒因素、化学因素、放射因素以及遗传因素。按起病的缓急可分为急、慢性白血病。儿童及青少年急性白血病多起病急骤。起病缓慢者以老年及部分青年病人居多,病情逐渐进展。研究表明,我国各地区白血病的发病率在各种肿瘤中占主导地位。
三氧化二砷是毒药“砒霜”的主要成分,其辛、大热,有大毒;归肺、肝经。外用攻毒杀虫,蚀疮去腐;内服劫痰平喘,截疟。是熟知的中药毒性药。中医药近几年来使用最多而且疗效最好的是用三氧化二砷治疗白血病。研究显示,其作用机制主要有降解融合蛋白、活化半胱氨酸激酶家族、影响Bcl-2蛋白家族、开放线粒体膜通透性转运孔、调节谷胱甘肽氧化还原***等。但是三氧化二砷临床应用剂量和安全剂量相近,在应用过程中易出现一些不良反应,从而限制了其在临床上的应用。
青蒿琥酯(Artesunate,ART)是青蒿素衍生物之一,除了抗疟疾作用,其抗肿瘤作用更是引起人们的广泛关注,临床应用前途广泛。近年来,国内外学者研究发现,ART可通过抑制肿瘤细胞增殖和诱导肿瘤细胞分化和凋亡、调控细胞信号转导、抑制肿瘤血管新生、抑制肿瘤侵袭转移、增敏抗肿瘤化疗药物及逆转耐药等多种机制发挥抗肿瘤作用。研究表明,应用ART作用NB4细胞,流式结果显示ART作用NB4细胞24h后即可引起细胞凋亡,且呈给药时间剂量依赖性,证实了ART能诱导NB4细胞凋亡。
发明内容
发明目的:本发明的目的在于提供一种增强砷剂治疗白血病的单体化合物
本发明提供的一种增强三氧化二砷治疗白血病的单体化合物可以制成任何临床上可以接受的剂型。
附图说明
附图1为ART与ATO及RA联用对模型小鼠生存时间的影响;
附图2为ART与ATO及RA联用对模型小鼠外周血GFP的影响;
图2-1为空白对照组;
图2-2为模型组;
图2-3为ATO组;
图2-4为ATO+RA组;
图2-5为ATO+ART组;
图2-6为ART+RA组;
图2-7为ATO+RA+ART组;
附图3为ART与ATO及RA联用对模型小鼠骨髓细胞CD34+/CD117+的影响;
图3-1为空白对照组;
图3-2为模型组;
图3-3为ATO组;
图3-4为ATO+RA组;
图3-5为ATO+ART组;
图3-6为ART+RA组;
图3-7为ATO+RA+ART组;
附图4为ART与ATO及RA联用对模型小鼠脏器损伤的影响;
图4-1为空白对照组;
图4-2为模型组;
图4-3为ATO组;
图4-4为ATO+RA组;
图4-5为ATO+ART组;
图4-6为ART+RA组;
图4-7为ATO+RA+ART组;
附图5为ART与ATO及RA联用NB4细胞相关蛋白的影响;
图5-1为NF-κB蛋白表达;
图5-2为Survivin蛋白表达;
图5-3为MMP-9蛋白表达;
图5-4为VEGF蛋白表达;
图5-5为β-actin蛋白表达。
具体实施例
具体实施例1
建立动物模型考察青蒿琥酯增强三氧化二砷联合为甲酸治疗APL的疗效
结果:ART 100mg/kg与ATO 2mg/kg及RA 7mg/kg联用干预APL模型小鼠后,能显著延长模型动物生存时间;ATO+RA、RA+ART、ATO+RA+ART组小鼠外周血GFP显著降低(P<0.05);ATO+RA、RA+ART、ATO+RA+ART组CD34+/CD117+阳性表达的细胞比例明显下降(P<0.05);可以显著改善模型动物的病理损伤程度。实验结果见表1、表2、表3、图1、图2、图3、图4。
表1.ART与ATO及RA联用对模型小鼠生存时间的影响(n=6)
#:与对照组比较P<0.05
表2.ART与ATO及RA联用对模型小鼠外周血GFP的表达的影响(n=6)
#:与模型组比较P<0.05
表3.ART与ATO及RA联用对模型小鼠骨髓细胞CD34+/CD117+的表达的影响(n=6)
#:与模型组比较P<0.05
具体实施例2
体外实验考察ART与三氧化二砷及维甲酸联用对NB4细胞相关蛋白的影响
结果:ART 0.4μM与ATO 1μM及RA 1μM联用干预NB4细胞后,与空白对照组比较,各给药组的NF-κB蛋白出现了下调表达,其中单用RA组下调较少,其余各组下调明显。
Survivin蛋白的表达结果显示,三药联用有效抑制了该蛋白的表达,但其余各给药组均无较大作用。MMP-9蛋白表达结果显示,ATO+ART、ART+RA、ATO+RA+ART四个给药组对MMP-9蛋白的表达起到了显著的抑制作用。见图5.
具体实施例3
MTT法测定As203对NB4细胞的细胞活力的影响
结果:As203剂量依赖性减弱细胞活力。As203对NB4细胞的半数抑制浓度IC50=2.00μM。实验结果见表4。
表4.MTT法测定As203对NB4细胞的细胞活力的影响(n=6)
##:与对照组比较P≤0.01
具体实施例4
MTT法测定青蒿琥酯对NB4细胞的细胞活力的影响
结果:与空白对照组比较,青蒿琥酯0.25、0.50、1.00、2.00、4.00μM组均可显著性的抑制NB4细胞增殖(P<0.01),且呈浓度依赖性,其半数抑制浓度为0.80μM,实验结果见表5。
表5.MTT法测定青蒿琥酯对NB4细胞的细胞活力的影响(n=6)
##:与对照组比较P≤0.01
具体实施例5
MTT法测定青蒿琥酯联合As203对NB4细胞的细胞活力的影响
结果:与空白对照组比较,0.4μM青蒿琥酯组细胞增值抑制率明显升高(P<0.05);1.0μM三氧化二砷组与空白对照组比较可使细胞增殖抑制率显著性升高(P<0.01)。三氧化二砷联合青蒿琥酯组较空白对照组可使细胞增殖抑制率极显著升高(P<0.01),见表6。
表6.MTT法测定青蒿琥酯联合As203对NB4细胞的细胞活力的影响(n=6)
##:与对照组比较P≤0.01;#:与对照组比较P<0.05
具体实施例6
三氧化二砷联合青蒿琥酯对NB4细胞周期的影响
结果:与空白对照组比较,1μM三氧化二砷组细胞G0/G1期细胞比例明显增加(P<0.01),S期细胞比例明显减少。0.4μM青蒿琥酯组NB4细胞周期较空白对照组无明显变化。0.4μM青蒿琥酯联合1μM三氧化二砷组细胞G0/G1期细胞比例明显增加,G2/M期细胞比例减少,见表7。
表7.三氧化二砷联合青蒿琥酯对NB4细胞周期的影响(n=3,)
##:与对照组比较P≤0.01
具体实施例7
三氧化二砷联合青蒿琥酯对NB4细胞凋亡的影响
结果:与空白对照组比较,0.4μM青蒿琥酯组NB4细胞凋亡率明显升高(P<0.05);
1μM三氧化二砷组NB4细胞凋亡率较空白对照组明极显著升高(P<0.01)。青蒿琥酯0.4μM联合三氧化二砷1μM组细胞凋亡率较空白对照组极显著升高(P<0.01),见表8。
表8.三氧化二砷联合青蒿琥酯对NB4细胞凋亡的影响(n=3,)
##:与对照组比较P≤0.01;#:与对照组比较P<0.05。
Claims (3)
1.一种增强砷剂治疗白血病的单体化合物,其特征在于:包括:青蒿素、双氢青蒿素、青蒿琥酯、蒿甲醚以及其他青蒿素类衍生物。
2.根据权利要求1所述的方法,其特征在于:青蒿琥酯可通过抑制肿瘤细胞增殖和诱导肿瘤细胞分化和凋亡、调控细胞信号转导、抑制肿瘤血管新生、抑制肿瘤侵袭转移、增敏抗肿瘤化疗药物及逆转耐药等多种机制发挥抗肿瘤作用,以实现ART作用NB4细胞24h后即可引起细胞凋亡,且呈给药时间剂量依赖性,以实现ART能诱导NB4细胞凋亡。
3.根据权利要求1所述的方法,其特征在于:可以制成任何临床上可以接受的剂型,包括化合物与三氧化二砷以外的砷剂两者联用,还包括化合物与三氧化二砷以外的其他砷剂的多种联用方法在治疗白血病方面的应用。
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