CN104398509B - CFTR抑制剂CFTRinh-172在制备防治白血病细胞介导的疾病的药物中的应用 - Google Patents
CFTR抑制剂CFTRinh-172在制备防治白血病细胞介导的疾病的药物中的应用 Download PDFInfo
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Abstract
本发明提供了一种CFTR抑制剂CFTRinh‑172在制备防治白血病细胞介导的疾病的药物中的应用。CFTRinh‑172通过抑制CFTR在核细胞中的高表达来有效抑制白血病细胞的增殖，为制备防治白血病细胞介导的疾病的药物提供了新途径。
Description
技术领域
本发明属于医药技术领域，具体涉及CFTR抑制剂CFTRinh-172在制备防治白血病细胞介导的疾病的药物中的应用。
背景技术
囊性纤维化跨膜传导调节因子(CFTR)的编码基因是造成囊性纤维化（CF）的主要因素，1989年首次被发现。CFTR的位点在第七对常染色体的长臂上（7q31），编码产物是由1480个氨基酸组成的一种cAMP调节的氯离子通道，是ABC(ATP-blndingeasoette)蛋白家族的一个成员。含有二个疏水的结构域，这二个结构均具有复杂的转膜部分，二个ATP结合结构域和一个细胞内结构域。CFTR基因是囊性纤维化穿膜传导调节因子，它能调节和促进上皮细胞膜电解质离子的转运。
囊性纤维化是由CFTR基因突变所致的常染色体隐性遗传病，主要病变为外分泌腺的功能紊乱，可使呼吸系统、肝胆、男性生殖系统、汗腺和胰腺受到损伤。慢性肺部症状加上肠吸收不良多可提示CF诊断。在胰腺，CFTR分布于导管系统的腔面细胞膜上，为cAMP调控的氯离子通道，使氯离子由胰腺导管细胞进入腺泡腔或导管腔，表达在人体许多上皮组织中。迄今为止，已发现CFTR有1 000种以上的突变和200多种多态性位点。这些突变和多态性可引起许多典型和不典型的囊性纤维化的不同表型。目前，对CFTR相关疾病谱的了解和认识主要在于肺部疾病和胰腺相关疾病。
在生理条件下，血细胞的增殖、分化、凋亡处于动态平衡，白血病是造血系统恶性肿瘤，其特征是造血细胞分化成熟受阻，未分化细胞大量增殖。近年来，许多研究证实白血病细胞可自发产生一些细胞因子，通过自泌环节作用于细胞本身的增殖。
现有技术中普遍使用的治疗白血病或者抑制白血病细胞增值的化疗药物，都存在非特异性的缺点，没有特异针对的靶点基因蛋白，例如柔红霉素等，常伴有毒副作用。因此，开发出具有特异性的靶点药物已非常迫切。
现有技术中还未见有将CFTR基因与白血病细胞增值相关的报道。
发明内容
本发明提供了一种CFTR抑制剂CFTRinh-172在制备防治白血病细胞介导的疾病的药物中的应用。
其结构式如下：
CFTRinh-172结构式
CFTRinh-172是电势差不依赖性的选择性CFTR抑制剂，Ki为300 nM，对于MDR1，ATP敏感性钾离子通道或者一系列的转运蛋白没有效果。CFTRinh-172通过抑制CFTR在核细胞中的高表达来有效抑制白血病细胞的增殖，为治疗白血病细胞介导的疾病提供了新途径。
本发明使用模式生物斑马鱼研究CFTR对造血的调控作用。发现早期发育的胚胎中CFTR的表达被抑制后造血前体细胞的标记基因的表达明显减弱；信号通路研究表明CFTR位于Wnt3（wingless-type MMTV integration site family, member 3A，无翅信号配体因子3，）的下游且正相关调控Wnt（Wingless，无翅）信号关键基因Dvl（Dishevelled，散乱蛋白）的表达；进一步的分子研究表明CFTR结合Dvl蛋白并保护Dvl蛋白免受溶酶体的降解，从而维持了wnt信号的转导。
由于wnt信号的异常表达与白血病的发病紧密相关。所以本发明根据在斑马鱼模型中的分子机理发现，检测了CFTR在白血病中作用。结果显示CFTR的异常表达于白血病的发病密切相关，在白血病细胞中CFTR存在较高水平的表达。对白血病细胞使用干扰RNA技术或者CFTR抑制剂处理，细胞皆出现增殖显著减弱并伴随细胞凋亡的现象。
根据SONAWANE et al (journal of pharmaceutical sciences, vol.94, No.1)报道在小鼠中使用高剂量的CFTRinh-172没有发现毒性反应；Thiagarajah（Clinicalpharmacology & Therapeutics，vol.92, No.3）报道CFTRinh-172因为肾脏最低程度新陈代谢的分泌而产生了很低的毒性。综合现在已有报道，考虑到CFTRinh-172是针对CFTR基因特异的小分子抑制剂，该药物几乎不会引起动物的毒性反应，具有很高的靶向性。
本发明首次报道了CFTR对造血的分子调控机理，并且为白血病的治疗提供了新的途径。CFTRinh-172是筛选获得的特异针对体内CFTR基因蛋白的抑制剂，在体内对其他的基因蛋白上没有靶点，并且在长期的使用过程中已经证明了其对CFTR基因蛋白功能抑制的有效性。特异针对CFTR基因蛋白功能的药物，并且作用的分子机理清晰。
附图说明
图1为实施例1的CFTR蛋白检测的免疫印迹结果图。
图2为实施例1的CFTR蛋白检测的免疫荧光结果图。
图3为实施例2的白血病细胞实验的结果图。
图4为实施例2的白血病细胞计数的结果数据图。
具体实施方式
下面结合具体实施方式对本发明的实质性内容作进一步详细的描述。
实施例1
CFTR蛋白检测血细胞增殖
具体步骤如下：
1.分别抽取白血病人（样本1）和非白血病人（样本2）的外周血1ml于抗凝的紫头或绿头管中保存，于当天进行单个核细胞的分离；
2.使用天津灏洋生物制品有限公司的人单个核细胞分离液分离外周血的单个核细胞，具体操作根据产品说明书；
3.一部分细胞加入非变性蛋白裂解液裂解单个核细胞，提取细胞的15ug总蛋白使用免疫印迹方法检测CFTR蛋白表达水平（beta-tubulin蛋白作为参照），另一部分于载玻片上涂片，使用免疫荧光检测CFTR蛋白表达水平；
4.对比CFTR基因蛋白表达水平，免疫印迹技术结果（图1）显示：样本2的 CFTR蛋白没有出现条带信号，表明血细胞处于较低增殖水平；样本1出现明显的信号，表明血细胞有异常增殖。
5.免疫荧光结果（图2）显示：样本1的部分血细胞出现CFTR蛋白表达，表明血细胞处于低水平增殖水平；样本2的全部血细胞都出现CFTR高表达，表明血细胞处于高度增殖状态。
免疫印迹和免疫荧光检测结果均显示：白血病人的样本1中CFTR蛋白出现了高表达，证明了CFTR蛋白与血细胞异常增殖密切相关。
实施例2
细胞培养
白血病细胞CCRF-CEM用含有10%小牛血清的1640培养基37摄氏度培养。
细胞实验
往含有细胞的培养基中加入CFTRinh-172至终浓度为50μm，对照组加入等体积的二甲基亚砜（DMSO）；处理72小时后对细胞进行计数，结果发现CFTRinh-172处理组细胞数量显著减少（图3和图4），表明CFTRinh-172对白血病细胞存在显著的抑制作用。
Claims (1)
1.CFTR抑制剂CFTRinh-172在制备防治白血病细胞介导的疾病的药物中的应用，其特征在于：所述的疾病为白血病，其中，CFTRinh-172的化学结构式为：
。
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