CN112891341A - Gl-v9与蒽环类抗生素在制备白血病治疗药物中的应用 - Google Patents
Gl-v9与蒽环类抗生素在制备白血病治疗药物中的应用 Download PDFInfo
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Abstract
本发明公开了黄酮类衍生物GL‑V9与蒽环类抗生素在制备白血病治疗药物中的应用，属于医药技术领域。本发明发现黄酮类衍生物GL‑V9联合低剂量的蒽环类抗生素能显著抑制急性髓系白血病（AML）细胞的生长，通过MTT实验以及U937细胞裸鼠移植瘤模型验证了GL‑V9与低剂量的蒽环类抗生素可发挥协同抗AML作用，提示这种联合给药方式在治疗AML中的应用潜力。
Description
技术领域
本发明属于医药技术领域，具体涉及GL-V9与蒽环类抗生素在制备白血病治疗药物中的应用。
背景技术
白血病是一类造血干细胞恶性克隆性疾病，俗称“血癌”。白血病细胞具有不受控制的增殖、分化异常、凋亡受阻等特点，因而得以在骨髓和其它造血组织中无限制地增殖和积聚，逐渐取代了正常的造血功能，使红细胞、白细胞等无法正常地产生和发挥作用，并浸润其它非造血组织和器官，从而引起一些列的症状、多器官功能衰竭，甚至死亡。白血病患者临床可见不同程度的贫血、出血，肝、脾、***肿大，感染发热以及骨骼疼痛。
黄酮类化合物GL-V9是对汉黄芩素进行结构优化黄酮类化合物的衍生物，由天然产物汉黄芩素经两步反应合成，首先在丙酮和K2CO3的反应条件下通过1,4-二溴丁烷取代汉黄芩素C7位上的酚羟基，然后吡咯烷取代上一步产物中的溴，最终得到GL-V9。
目前白血病的疗法主要有化疗、放疗、免疫疗法、造血干细胞移植等，还没有出现GL-V9与其他药物联合应用治疗白血病的报道。
发明内容
本发明的目的是提供了GL-V9与蒽环类抗生素在制备白血病治疗药物中的应用。
GL-V9与蒽环类抗生素在制备白血病治疗药物中的应用。
进一步地，所述蒽环类抗生素为柔红霉素。
进一步地，所述白血病为急性髓细胞白血病AML。
一种白血病治疗药物，包括GL-V9和蒽环类抗生素，所述蒽环类抗生素为柔红霉素。
进一步地，所述白血病为急性髓细胞白血病AML。
进一步地，所述治疗药物中GL-V9的浓度为2-4μM，柔红霉素的浓度为0.1nM。
所述白血病治疗药物还可包括可接受的辅料。
所述可接受的辅料可为赋形剂、填充剂、粘合剂、湿润剂、吸收促进剂或润滑剂。
所述白血病治疗药物可采用本领域的常规方法制成各种剂型，包括汤剂、片剂、胶囊剂、针剂、粉针剂、颗粒剂、冲剂、口服液和糖浆剂等。
本发明发现黄酮类衍生物GL-V9联合低剂量的蒽环类抗生素能显著抑制急性髓系白血病(AML)细胞的生长。通过MTT实验以及U937细胞裸鼠移植瘤模型验证了GL-V9与低剂量的蒽环类抗生素可发挥协同抗AML作用，提示这种联合给药方式在治疗AML中的应用潜力。
附图说明
图1为实施例1中GL-V9联合柔红霉素对AML细胞株Kasumi-1生长的影响结果。
具体实施方式
下面结合附图和具体实施例对本发明作进一步详细说明，但不应理解为对本发明的限制。在不背离本发明精神和实质的情况下，对本发明方法、步骤或条件所作的修改或替换，均属于本发明的范围。实施例中未注明具体条件的实验方法及未说明配方的试剂均为按照本领域常规条件。
本发明所述黄酮类衍生物GL-V9的结构式如下式所示：
实施例1
GL-V9联合柔红霉素对人AML细胞生长的影响
1、试剂
(1)GL-V9(C24H27O5N，分子量：409.47)由中国药科大学提供，淡黄色粉末，纯度大于99％，使用前用二甲亚砜(DMSO)将药物粉末配制为0.02M母液，置于-20℃保存。柔红霉素注射剂由南京鼓楼医院提供，避光保存。所有试剂临用前用含10％胎牛血清的RPMI-1640培养液配成所需浓度。
(2)细胞培养试剂
①培养液：RPMI-1640培养基，购自美国GIBCO公司。取RPMI-1640粉末10.39g溶于1000mL灭菌三蒸水中，并加入2.0g NaHCO3，用1M盐酸调pH值至7.0，圆筒式过滤器过滤除菌、分装，4℃冰箱保存。使用前加入100U/mL的青霉素和100U/mL的链霉素。
②胎牛血清：美国GIBCO公司产品。经56℃水浴灭活30min，分装并保存于-20℃低温冰箱中。
③PBS缓冲液：称取NaCl 8.0g、KCl 0.20g、Na2HPO4·H2O 1.56g、KH2PO4.2.0g，溶于1000mL三蒸水中，高压灭菌，4℃冰箱保存。
(3)细胞生长活力抑制检测相关试剂
MTT粉末购自Sigma-Aldrich公司。
2、细胞株
人AML细胞株Kasumi-1均购自上海中国科学院细胞所。细胞均用含100U/mL青霉素、100mg/mL链霉素和10％胎牛血清的RPMI1640培养液培养。
3、实验方法
MTT溶液能够被活细胞内的线粒体脱氢酶还原为蓝紫色的结晶甲臜，DMSO可溶解甲臜，形成的溶液颜色深浅与细胞活力成正比，据此可以检测细胞的活力。将细胞按照合适的细胞密度培养在96孔酶标板内，每孔内的细胞体积为100μL，同时在其中加入100μL指定浓度的GL-V9和柔红霉素；将给过药物的细胞继续置于孵箱培养24h后，每孔加入20μL MTT溶液；继续孵育4h后将上清液移除，每孔加入100μL DMSO，置于微型振荡器振荡，待结晶完全溶解后，使用570nm波长检测其吸光度。将检测后的吸光值整理后按下面的公式计算药物对细胞的生长抑制率：
通过MTT实验测定24h时间点天然产物衍生物GL-V9联合柔红霉素对AML细胞系Kasumi-1生长的抑制作用。如图1所示，相较于柔红霉素单用组，GL-V9联合柔红霉素显著抑制AML细胞Kasumi-1细胞的生长，该结果初步证实了GL-V9联合化疗药抗AML的作用。
实施例2
GL-V9联合柔红霉素对U937细胞裸鼠移植瘤的影响
1、受试药物
(1)GL-V9(C24H27O5N，分子量：409.47)由中国药科大学提供，淡黄色粉末，纯度大于99％，气流粉碎后，常温保存。给药时，称取药物粉末，用0.5％的CMC-Na溶液混悬使用，按体重0.2mL/20g灌胃给药。
(2)注射用盐酸柔红霉素由南京鼓楼医院提供，避光保存。临用前用生理盐水配成所需浓度，尾静脉注射给药。
2、细胞株
人AML细胞株U937购自上海中国科学院细胞所。所用细胞用含100U/mL青霉素、100mg/mL链霉素和10％胎牛血清的RPMI1640培养液培养。
3、实验动物
来源、种系、品系：BALB/c裸小鼠，由常州卡文斯实验动物有限公司(实验动物生产许可证：SCXK(苏)2016-0010)。饲养于中国药科大学实验动物中心SPF级动物房，饲养条件：温度23±2℃，相对湿度55±5％。
周龄：6w
体重：16-18g
性别：雌性。
4、实验方法
U937细胞裸鼠皮下移植瘤模型的建立
取对数生长期的人AML细胞U937细胞株，在无菌条件下制备成5×106/mL细胞悬液，与Matrigel胶1：1混合后，以0.1mL接种于裸鼠右侧腋窝皮下。接种后第6天开始给药，将裸鼠随机分为4组，每组6只分别为：(1)生理盐水对照组；(2)阳性药柔红霉素组(1.5mg/kg)，每隔2天给药1次；(3)GL-V9组(300mg/kg)，每天灌胃给药；(4)GL-V9(300mg/kg)联合柔红霉素(1.5mg/kg)组。给药体积为0.2mL/20g，给药周期14天，小鼠处死，手术剥取瘤块称重。
抑瘤率计算公式如下：
Tweight：治疗组平均瘤重；Cweight：阴性对照组平均瘤重。
药物GL-V9、低剂量阳性药柔红霉素以及两者联合对人AML细胞U937裸小鼠移植瘤的实验性治疗结果见表1。实验结果如下，药物GL-V9以300mg/kg灌胃给药，每天给药，共给药14天后，对人AML细胞U937裸小鼠移植瘤的抑瘤率达60.12％。柔红霉素以1.5mg/kg静脉注射给药，每3天给药1次，共给药5次后，对人AML细胞U937裸小鼠移植瘤的抑瘤率达48.87％。GL-V9联合柔红霉素显著抑制AML细胞U937的生长，对人AML细胞U937裸小鼠移植瘤的抑瘤率达73.96％。该结果初步证实了GL-V9联合化疗药抗AML的作用。
表1.药物GL-V9对人AML细胞U937裸鼠异种移植肿瘤生长的抑制作用(X±SD)
p1：与空白对照组比较；p2：与GL-V9单用组比较；p3：与柔红霉素单用组比较。
Claims (6)
1.GL-V9与蒽环类抗生素在制备白血病治疗药物中的应用。
2.根据权利要求1所述的应用，其特征在于：所述白血病为急性髓细胞白血病AML。
3.根据权利要求1所述的应用，其特征在于：所述蒽环类抗生素为柔红霉素。
4.一种白血病治疗药物，其特征在于：所述药物包括GL-V9和蒽环类抗生素，所述蒽环类抗生素为柔红霉素。
5.根据权利要求4所述的白血病治疗药物，其特征在于：所述白血病为急性髓细胞白血病AML。
6.根据权利要求4所述的白血病治疗药物，其特征在于：所述治疗药物中GL-V9的浓度为2-4µM，柔红霉素的浓度为0.1nM。
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| CN108354932A (zh) * | 2018-04-24 | 2018-08-03 | 中国药科大学 | 黄酮类化合物gl-v9在制备抗白血病药物中的应用 |
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