CN116492342A - 氯喹或羟氯喹在制备治疗尼洛替尼肾脏毒副作用药物中的应用 - Google Patents
氯喹或羟氯喹在制备治疗尼洛替尼肾脏毒副作用药物中的应用 Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
本发明公开了氯喹或羟氯喹在制备治疗尼洛替尼肾脏毒副作用药物中的应用,属于医药技术领域。本发明提供了氯喹及其衍生物在制备治疗尼洛替尼诱发肾脏毒性药物方面的新用途,通过与尼洛替尼联合用药可减轻肿瘤患者由于尼洛替尼使用带来的肾脏功能损伤,提高尼洛替尼用药安全性,很大程度上扩大了尼洛替尼的临床使用。氯喹及其衍生物是临床上已经长期使用的药物,安全性高,临床可行性强。
Description
技术领域
本发明涉及医药技术领域,具体涉及氯喹或羟氯喹在制备治疗尼洛替尼肾脏毒副作用药物中应用的新用途。
背景技术
尼洛替尼(Nilotinib,达希纳)是第二代酪氨酸激酶抑制剂,目前已被批准用于费城染色体阳性慢性髓系白血病的一线治疗。临床研究表明尼洛替尼对46%伊马替尼耐药的病人有效,且副作用更小。然而在临床使用过程中,有17%的患者服用尼洛替尼后经历了全级别的肾脏毒性,其中本身确诊为肾功能异常的患者出现肾脏毒性的概率高达78%,更有进展至Ⅲ/Ⅳ级肾脏毒性的风险(Sasaki K,et al.Clinical Safety and Efficacy ofNilotinib or Dasatinib in Patients With Newly Diagnosed Chronic-Phase ChronicMyelogenous Leukemia and Pre-Existing Liver and/or Renal Dysfunction.ClinLymphoma Myeloma Leuk 2016,16(3):152-62.)。尼洛替尼在临床应用中存在严重肾脏损伤的风险,限制其长期安全应用。
目前可治疗尼洛替尼肾脏毒性的有效手段十分匮乏,临床上通常采用减药或停药,导致肿瘤患者延误治疗时机。如何解决肾脏毒性问题是目前尼洛替尼临床应用中面临的重大问题,寻找肾脏毒性保护剂对于尼洛替尼临床安全广泛应用具有非常重要的现实意义。
氯喹(chloroquine)及其衍生物羟氯喹(hydroxychloroquine)是临床上长期用于治疗疟疾及自身免疫性疾病的药物,具有良好的临床安全性。研究显示氯喹衍生物具有抑制自噬、抗炎、免疫调节及抗癌等作用。
相关研究表明氯喹衍生物可以用于狼疮性肾炎的治疗,有效缓解肾小球炎症样损伤。此外,专利文献CN 113855674 A公开低剂量(具体为1μM)的氯喹氯喹可以通过转录上调肾脏中有机阴离子转运蛋白并抑制与CXCR有关的炎症趋化基因的表达而保护老年小鼠的肾脏衰老相关表型(炎症反应、纤维化等)。目前尚无氯喹衍生物用于治疗尼洛替尼引发肾脏毒性的报道。
课题组在前期研究中发现,尼洛替尼诱导抗凋亡蛋白Bcl-XL的过度泛素蛋白酶体通路降解是其引发肾脏毒性的关键原因,目前尚无Bcl-XL相关激动剂的报道。
发明内容
本发明的目的在于提供一种能够用于缓解尼洛替尼用药所诱发的肾脏毒性反应的药物,通过联合用药以减轻尼洛替尼单独用药引起的肾脏毒性副作用。
为实现上述目的,本发明采用如下技术方案:
本发明提供了氯喹或羟氯喹在制备治疗尼洛替尼引发的肾脏毒副作用的药物中的应用。
具体的,氯喹的CAS号为54-05-7,化学名为氯喹盐基4-(4-二乙氨基-1-甲基丁氨基)-7-氯喹啉,分子式为C18H26ClN3;羟氯喹的CAS号为118-42-3,化学名为2-[[4-[(7-氯喹啉-4-基)氨基]戊基](乙基)氨基]乙醇,分子式为C18H26ClN3O。
所述尼洛替尼引发的肾脏毒副作用表现为肾脏组织出现肾小球萎缩、肾小管扩张、肾小管间质纤维化等肾脏损伤。
本发明研究表明:尼洛替尼给药导致肾脏细胞中抗凋亡蛋白Bcl-XL显著下调,尼洛替尼通过促进Bcl-XL的泛素化修饰进而诱导Bcl-XL的过度泛素蛋白酶体通路降解,导致肾脏毒性。通过在肾脏细胞中过表达Bcl-XL可以逆转尼洛替尼引发的肾脏毒性。进一步在临床药物库筛选中发现氯喹及其衍生物羟氯喹可以逆转Bcl-XL的过度降解,恢复细胞中Bcl-XL蛋白水平进而干预尼洛替尼诱发的肾脏毒性。
具体的,氯喹或羟氯喹通过抑制尼洛替尼导致的Bcl-XL过度泛素蛋白酶体通路降解,从而缓解尼洛替尼引发的肾脏毒副作用。
利用氯喹或其衍生物与尼洛替尼联合用药能够显著抑制尼洛替尼诱导的Bcl-XL下调,逆转因Bcl-XL过度降解导致的肾脏损伤。因此,采用氯喹或羟氯喹与尼洛替尼联用将是减轻尼洛替尼肾脏毒性的有效途径。
动物实验表明,所述药物中氯喹或羟氯喹的有效剂量为20-40mg/kg。该用药剂量为安全有效剂量。
优选的,所述药物还包括药物上可接受的载体。
本发明的另一个目的是提供一种抗肿瘤联合用药物,包括氯喹或羟氯喹和药学上可接受的载体形成的第一制剂,及尼洛替尼和药学上可接受的载体形成的第二制剂。
本发明针对尼洛替尼引发的肾脏毒性,提供了一种有效的治疗药物。动物实验结果表明,与尼洛替尼单用组相比,合用氯喹或羟氯喹可逆转单用尼洛替尼引起的肾脏损伤生化标记物的升高。此外,氯喹或羟氯喹给药对动物存活、肾脏功能等情况无影响,且不影响尼洛替尼的抗癌效应,说明氯喹及其衍生物作为保护剂是合理且安全的。
优选的,所述药物中氯喹或羟氯喹有效剂量为20-40mg/kg。更为优选,所述药物中氯喹或羟氯喹有效剂量为30mg/kg。
优选的,所述药学上可接受的载体为填充剂、润湿剂、粘合剂、崩解剂或润滑剂。
所述药物的剂型为液体制剂或固体制剂,优选的,所述药物的制剂形式为口服制剂。
本发明还提供了所述的抗肿瘤联合用药物在制备治疗慢性粒细胞白血病的药物中的应用。
所述慢性粒细胞白血病可以为但不限于费城染色体阳性慢性髓系白血病。
本发明具备的有益效果:
(1)本发明提供了氯喹及其衍生物羟氯喹在制备治疗尼洛替尼诱发肾脏毒性药物方面的新用途。氯喹及其衍生物羟氯喹通过与尼洛替尼联合用药可减轻肿瘤患者由于尼洛替尼使用带来的肾脏功能损伤,提高尼洛替尼用药安全性,很大程度上扩大了尼洛替尼的临床使用。
(2)氯喹和羟氯喹是目前临床上长期用于治疗疟疾及自身免疫性疾病的药物,安全性高,临床可行性强。
(3)本发明提供了尼洛替尼肾脏毒性的发生机制,即尼洛替尼诱导抗凋亡蛋白Bcl-XL的过度泛素蛋白酶体通路降解,为尼洛替尼引起肾脏毒性的临床研究提供了理论依据,有利于治疗药物的筛选研发。
附图说明
图1为western blot法考察尼洛替尼对肾脏组织Bcl-XL蛋白水平的影响(A)以及在HK-2细胞中过表达Bcl-XL对尼洛替尼毒性的影响(B)。
图2为western blot法考察尼洛替尼作用下Bcl-XL泛素化修饰的改变以及氯喹对这一过程的影响(A)以及在HK-2细胞中氯喹对尼洛替尼作用后Bcl-XL和凋亡标记物c-PARP的影响(B)。
图3为western blot法考察合用羟氯喹后尼洛替尼诱导的HK-2细胞中Bcl-XL和c-PARP的变化。
图4为western blot法考察合用羟氯喹后尼洛替尼诱导的肾脏组织中Bcl-XL变化,其中左图为western blot结果,右图为结果统计图。
图5为合用羟氯喹后尼洛替尼诱导的小鼠血清中肾脏损伤生化标记物的水平,其中A为血尿素氮(BUN);B为血清肌酐(Scr)。
图6为合用羟氯喹后小鼠肾脏组织损伤变化情况,其中A为苏木精-伊红染色(HE);B为Masson三色染色(Masson’s trichrome);C为天狼星红染色(Sirius red)。
图7为合用氯喹或羟氯喹后对尼洛替尼抗癌效应的影响,其中A为合用氯喹,B为合用羟氯喹。
具体实施方式
下面结合具体实施例对本发明做进一步说明。以下实施例仅用于说明本发明,不用来限制本发明的适用范围。在不背离本发明精神和本质的情况下,对本发明方法、步骤或条件所做的修改或替换,均属于本发明的范围。
下述实施例中所使用的试验方法如无特殊说明,均为常规方法;所使用的材料、试剂等,如无特殊说明,为可从商业途径得到的试剂和材料。
C57BL/6J小鼠购买自上海斯莱克实验动物有限责任公司;HK-2细胞购买自中国科学院上海生命科学研究院细胞资源中心;K562细胞购买自北京协和细胞资源中心;羧甲基纤维素钠(CMC-Na)、MG-132购买自Sigma-Aldrich公司;Bcl-XL、c-PARP抗体购自华安生物科技有限公司;ACTB、GAPDH、HA抗体购自杭州戴格生物技术有限公司;FLAG抗体购买自上海七纯生物科技有限公司;Anti-FLAG beads购买自天地人和生物有限公司;CCK-8检测试剂盒购买自碧云天生物技术有限公司。
氯喹,CAS号为54-05-7,化学名为氯喹盐基4-(4-二乙氨基-1-甲基丁氨基)-7-氯喹啉,分子式为C18H26ClN3,分子量为319.89,购买自Selleck Chemicals公司,结构式如下:
羟氯喹,CAS号为118-42-3,化学名为2-[[4-[(7-氯喹啉-4-基)氨基]戊基](乙基)氨基]乙醇,分子式为C18H26ClN3O,分子量为335.87,购买自TCI公司,结构式如下:
实施例1
10只雄性C57BL/6J小鼠,随机分成2组,分别为对照组、尼洛替尼组,每组6只,以灌胃的方式给药。尼洛替尼给予的剂量为300mg/kg/day,对照组给予0.5%CMC-Na溶液。连续给药30天后,处死小鼠,剖取肾脏,取部分肾脏组织样本裂解提取蛋白,利用western blot法考察Bcl-XL蛋白水平。
Western blot结果如图1中(A)所示,尼洛替尼作用下,肾脏组织中抗凋亡蛋白Bcl-XL水平明显下调。表明尼洛替尼通过下调Bcl-XL引起肾脏毒性。
实施例2
根据已有文献报道,我们使用人肾皮质近曲小管上皮细胞(HK-2)作为体外细胞模型,在HK-2细胞中,利用质粒转染技术过表达pcDNA3.0-Bcl-XL-FLAG(Gene ID:NM_138578.1)和空载质粒24小时后,继续给予8μM尼洛替尼处理24小时,收样,裂解细胞,利用western blot法考察Bcl-XL和凋亡标记蛋白c-PARP的变化。
Western blot结果如图1中(B)所示,在HK-2细胞中,利用质粒转染技术成功实现了Bcl-XL的过表达,Bcl-XL的蛋白水平显著升高;在同时给予尼洛替尼处理的条件下,过表达Bcl-XL组的c-PARP蛋白水平相较于过表达空载组的c-PARP蛋白水平显著下降。表明过表达Bcl-XL可以显著逆转尼洛替尼肾脏毒性。
实施例3
在HEK-293T细胞中,利用质粒转染技术过表达Bcl-XL-FLAG和Ubiquitin-HA质粒24小时后,给予8μM尼洛替尼和/或10μM氯喹处理24小时,在收样前8小时加入26S蛋白酶体抑制剂MG-132处理,裂解细胞,使用Anti-FLAG beads进行免疫共沉淀实验,利用westernblot法考察与Bcl-XL结合的泛素蛋白水平变化。
Western blot结果如图2中(A)所示,单给尼洛替尼组与对照组相比,与Bcl-XL结合的泛素蛋白数量显著增加;合用氯喹组与单给尼洛替尼组相比,与Bcl-XL结合的泛素蛋白数量明显减少。表明尼洛替尼促进了Bcl-XL的泛素化修饰,而氯喹可以逆转这一过程。
实施例4
在HK-2细胞中,给予8μM尼洛替尼和/或10μM氯喹处理24小时后,收样,裂解细胞,利用western blot法考察Bcl-XL和c-PARP蛋白的变化。
Western blot结果如图2中(B)所示,单给尼洛替尼组与对照组相比,Bcl-XL的蛋白水平显著下降,而c-PARP水平显著升高;合用氯喹组与单给尼洛替尼组相比,Bcl-XL蛋白水平能恢复至正常,c-PARP水平也显著下调。表明氯喹可以通过逆转尼洛替尼诱导的Bcl-XL过度泛素蛋白酶体通路降解而干预尼洛替尼的肾脏毒性。
实施例5
在HK-2细胞中,给予8μM尼洛替尼和/或10μM羟氯喹处理24小时后,收样,裂解细胞,利用western blot法考察Bcl-XL和c-PARP蛋白的变化。
Western blot结果如图3所示,单给尼洛替尼组与对照组相比,Bcl-XL的蛋白水平显著下降,而c-PARP水平显著升高;合用羟氯喹组与单给尼洛替尼组相比,Bcl-XL蛋白水平能恢复至正常,c-PARP水平也显著下调。表明羟氯喹与氯喹有相似的药理学效应,可以干预尼洛替尼的肾脏毒性。
实施例6
20只雄性C57BL/6J小鼠,随机分成4组,分别为对照组、尼洛替尼组、羟氯喹组、尼洛替尼+羟氯喹合用组,每组5只,以灌胃的方式给药。尼洛替尼给予的剂量为300mg/kg/day,羟氯喹给予的剂量为30mg/kg/day,对照组用0.5%CMC-Na溶液代替。连续给药30天后,采用眼眶取血,检测血清中肾脏损伤生化标记物血尿素氮(BUN)和血清肌酐(Scr)值,随后处死小鼠,剖取肾脏,取部分肾脏组织样本裂解提取蛋白,利用western blot法考察Bcl-XL蛋白水平,对剩余肾脏组织进行包埋、切片、HE染色、Masson’s trichrome染色、Sirius red染色。
Western blot结果如图4所示,尼洛替尼作用下,小鼠肾脏组织中Bcl-XL蛋白水平由对照组的(1.04±0.12)倍下调至(0.31±0.08)倍,水平显著下降,合用羟氯喹后,Bcl-XL水平回升至(0.57±0.12)倍。表明羟氯喹可以通过阻止尼洛替尼诱导的Bcl-XL下调进而干预尼洛替尼肾脏毒性。
血液生化结果如图5所示,尼洛替尼作用下,小鼠血清中BUN由对照组的(15.18±0.79)mmol/L升高至(37.70±6.94)mmol/L,Scr由对照组的(23.40±1.14)μmol/L升高至(58.00±10.15)μmol/L,合用羟氯喹后,小鼠血清中BUN降至(24.12±2.72)mmol/L,Scr降至(36.20±4.97)μmol/L,均接近于对照组水平。表明羟氯喹可以显著改善尼洛替尼引起的肾脏功能异常。
HE染色结果如图6中(A)所示,尼洛替尼作用下,肾脏组织出现明显的肾小球萎缩、肾小管扩张,合用羟氯喹可以显著改善这些症状。表明羟氯喹可以逆转尼洛替尼引起的肝脏器质性损伤。Masson’s trichrome染色与Sirius red染色结果如图6中(B)、(C)所示,尼洛替尼作用下,肾脏组织肾小管间质中出现明显的胶原沉积,表征肾脏纤维化的出现,合用羟氯喹可以逆转这些症状。表明羟氯喹可以逆转尼洛替尼引起的肾脏纤维化表型。
实施例7
在BCR-ABL+的人白血病细胞系K562中,给予30nM尼洛替尼和/或10μM氯喹(羟氯喹)处理24小时后,通过CCK-8实验检测细胞活力。
CCK-8检测结果如图7所示,单给尼洛替尼后K562细胞活力下降至(49.75±6.64)%或(47.03±6.54)%,而合用氯喹后,K562细胞活力变为(39.73±6.86)%,合用羟氯喹后,K562细胞活力变为(41.72±4.60)%,无显著性差异。表明合用氯喹衍生物不会影响尼洛替尼的抗癌效应。
Claims (10)
1.氯喹或羟氯喹在制备治疗尼洛替尼引发的肾脏毒副作用的药物中的应用。
2.如权利要求1所述的应用,其特征在于,氯喹或羟氯喹通过抑制尼洛替尼导致的Bcl-XL过度泛素蛋白酶体通路降解,从而缓解尼洛替尼引发的肾脏毒副作用。
3.如权利要求1所述的应用,其特征在于,所述药物中氯喹或羟氯喹的有效剂量为20-40mg/kg。
4.一种抗肿瘤联合用药物,其特征在于,包括氯喹或羟氯喹和药学上可接受的载体形成的第一制剂,及尼洛替尼和药学上可接受的载体形成的第二制剂。
5.如权利要求4所述的抗肿瘤联合用药物,其特征在于,所述药物中氯喹或羟氯喹有效剂量为20-40mg/kg。
6.如权利要求5所述的抗肿瘤联合用药物,其特征在于,所述药物中氯喹或羟氯喹有效剂量为30mg/kg。
7.如权利要求4所述的抗肿瘤联合用药物,其特征在于,所述药学上可接受的载体为填充剂、润湿剂、粘合剂、崩解剂或润滑剂。
8.如权利要求4所述的抗肿瘤联合用药物,其特征在于,所述药物的制剂形式为口服制剂。
9.如权利要求4-8任一项所述的抗肿瘤联合用药物在制备治疗慢性粒细胞白血病的药物中的应用。
10.如权利要求9所述的应用,其特征在于,所述慢性粒细胞白血病为费城染色体阳性慢性髓系白血病。
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