CN115212211B - 双去甲基汉防己甲素双甲酸乙酯与parp-1抑制剂联合治疗肿瘤的用途 - Google Patents
双去甲基汉防己甲素双甲酸乙酯与parp-1抑制剂联合治疗肿瘤的用途 Download PDFInfo
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Abstract
本发明公开了一种双去甲基汉防己甲素双甲酸乙酯(W18)与聚腺苷二磷酸核糖聚合酶‑1(PARP‑1)抑制剂联合治疗肿瘤的用途,特别是用于制备耐药性卵巢癌药物中的用途,及它们的药物组合物。该联合用药具有协同增敏和耐药逆转作用,可显著提高治疗效果。
Description
技术领域
本发明属于医药技术领域,具体涉及一种新型汉防己甲素衍生物双去甲基汉防己甲素双甲酸乙酯(W18)与聚腺苷二磷酸核糖聚合酶-1(PARP-1)抑制剂联合治疗肿瘤的用途,特别是用于制备治疗耐药性卵巢癌药物中的用途。
背景技术
卵巢癌是当前女性三大常见的癌症类型之一,其发病率及死亡率在女性所有癌症中排名第八,晚期卵巢癌5年生存率仅30%左右,严重威胁女性健康(Hyuna S等, CA CancerJ Clin, 2021, 71(3):209-249.)。
新型抗肿瘤药物聚腺苷二磷酸核糖聚合酶-1(PARP-1)抑制剂通过协同致死效应发挥抗肿瘤作用。研究发现,约10%的卵巢癌的发病与抑癌基因BRCAl/2的遗传突变有关。BRCA突变导致DNA同源重组修复功能出现损害,肿瘤细胞的DNA双链断裂修复功能受损,故DNA修复途径将依赖于聚腺苷二磷酸核糖聚合酶-1(PARP-1)介导DNA单链断裂的修复以维持DNA的存活,而PARP-1抑制剂可以特异性地抑制PARP-1,阻断DNA修复进程,以致细胞DNA不能被重组修复而死亡(wang YQ等,J Med Chem,2016,59(21):9575-9598.)。
目前已有奥拉帕尼(Olaparib)、鲁卡帕尼(Rucaparib)、尼拉帕尼(Niraparib)、他拉唑帕尼(Talazoparib)和氟唑帕尼(Fluzoparib)等多款PARP-1抑制剂被批准上市或处于临床研究阶段。奥拉帕尼(结构式如下)由AstraZeneca公司研发,于2014年由FDA批准上市,是第一款批准上市的口服靶向晚期卵巢癌PARP-1抑制剂,临床应用需要检测 BRCA 突变。由Merck Sharp&Dohme等共同研发的尼拉帕尼(结构式如下)于2017年FDA批准上市,是首个无需BRCA突变或其他生物标志物检测,即可用的PARP抑制剂,适用人群更为广泛。但与其他靶向抗肿瘤药物一样,随着奥拉帕尼、尼拉帕尼等的应用,部分患者由于多种已知和未知因素对PARP-1抑制剂的治疗表现出耐药,限制了奥拉帕尼、尼拉帕尼等在临床上的更广泛应用和疗效(Konstantinopoulos PA等,Cancer Discov,2015,5(11):1137-1154.)。当前临床中研究探索了多种药物组合治疗方法来克服PARP-1抑制剂单用出现的耐药性问题。
双苄基异喹啉生物碱汉防己甲素是防己科汉防己根部的主要活性成分(结构式如下所示),研究表明,汉防己甲素及其溴代衍生物能通过抑制Pgp、调控凋亡信号通路等机制逆转肿瘤多药耐药,恢复耐药肿瘤细胞对抗癌药物的敏感性(Wang G等,Life Sci, 1995,56(5):295-06;Liu XD等,Cancer Lett, 2010,292(1):24-31.)。双去甲基汉防己甲素双甲酸乙酯(见下结构式W18,以下本文简称为“W18”化合物)为新型汉防己甲素衍生物。
发明内容
本发明人发现双去甲基汉防己甲素双甲酸乙酯(在本文中的代码称为W18)在低浓度如0.10µM~1.0µM单独使用时无抗肿瘤活性,但是经过进一步的深入研究,意外发现W18化合物可通过抑制药物外排蛋白Pgp、影响凋亡信号通路,在与聚腺苷二磷酸核糖聚合酶-1(PARP-1)抑制剂联用时能显著增强聚腺苷二磷酸核糖聚合酶-1(PARP-1)抑制剂的抗肿瘤活性。
为实现本发明的目的,提供如下实施方案。
本发明的一种双去甲基汉防己甲素双甲酸乙酯(W18)与PARP-1抑制剂联用在制造治疗肿瘤药物的用途。
优选的,上述本发明的用途,所述肿瘤为耐药性肿瘤,更优选为耐药性卵巢癌。
优选的,上述本发明的用途,所述联用是指不分先后间隔给药或同时给药,或以固定剂量形式给药。
优选的,上述本发明的用途,所述聚腺苷二磷酸核糖聚合酶-1(PARP-1)抑制剂选自奥拉帕尼、鲁卡帕尼、尼拉帕尼、他拉唑帕尼和氟唑帕尼,优选为奥拉帕尼或尼拉帕尼。
优选的,上述本发明的用途,所述双去甲基汉防己甲素双甲酸乙酯(W18)与奥拉帕尼或尼拉帕尼的摩尔比为(0.10~1.0):(10~100)。
本发明的目的还提供了一种用于治疗耐药性肿瘤的药物组合物,包含双去甲基汉防己甲素双甲酸乙酯(W18)、PARP-1抑制剂和药学上可接受的药用辅料。
优选的,上述本发明的药物组合物,其制剂形式为口服片剂、颗粒剂、胶囊、注射剂或复合包装。
优选的,上述本发明的药物组合物,所述肿瘤为耐药性卵巢癌。
上述本发明的药物组合物,所述聚腺苷二磷酸核糖聚合酶-1(PARP-1)抑制剂选自奥拉帕尼(Olaparib)、鲁卡帕尼(Rucaparib)、尼拉帕尼(Niraparib)、他拉唑帕尼(Talazoparib)或氟唑帕尼(Fluzoparib)等。
优选地,上述本发明的药物组合物,其中所述聚腺苷二磷酸核糖聚合酶-1(PARP-1)抑制剂选自奥拉帕尼(Olaparib)、尼拉帕尼(Niraparib)。
上述本发明的用途和药物组合物,所述双去甲基汉防己甲素双甲酸乙酯(W18)的结构式如下:
。
上述本发明的药物组合物,所述奥拉帕尼的结构式如下:
。
上述本发明的药物组合物,所述尼拉帕尼的结构式如下:
。
上述本发明的用途或药物组合物,其中W18与聚腺苷二磷酸核糖聚合酶-1 (PARP-1)抑制剂的物质的量之比为0.10~1.0:10~100 。
优选地,所述W18与聚腺苷二磷酸核糖聚合酶-1(PARP-1)抑制剂的物质的量之比为0.50~1.0:10~50 。
上述本发明的药物组合物,其制剂形式可以为口服片剂、颗粒剂、胶囊、注射剂。
上述本发明的药物组合物,所述药学上可接受的药用辅料为本领域常用辅料,填充剂如磷酸氢钙、淀粉、微晶纤维素、乙基纤维素、甘露醇、乳糖等,崩解剂如预胶化淀粉、羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮,粘合剂如低取代羟丙纤维素、乙醇、水、聚维酮等,润滑剂如滑石粉、硬脂酸镁等。制剂的制备方法可以为本领域常规制备方法制备。
本发明提供的双去甲基汉防己甲素双甲酸乙酯(W18)和与聚腺苷二磷酸核糖聚合酶-1(PARP-1)抑制剂,如奥拉帕尼(Olaparib)、鲁卡帕尼(Rucaparib)、尼拉帕尼(Niraparib)、他拉唑帕尼(Talazoparib)或氟唑帕尼(Fluzoparib)联合使用时,产生了明显的协同增敏作用,增强PARP-1抑制剂的抗肿瘤活性和作用,特别是对耐药卵巢癌的协同增敏作用最显著。
具体实施方式
以下实施例用于进一步理解本发明的协同增效作用效果,但不应以此限制本发明的范围。
实施例1
W18联用奥拉帕尼或尼拉帕尼对内在耐药卵巢癌OVCAR5细胞毒性的协同增效作用
MTT法检测奥拉帕尼、尼拉帕尼单独或联用W18对内在耐药的卵巢癌OVCAR5细胞的细胞毒性:3000个/孔的对数生长期的OVCAR5细胞接种于96孔培养板内,过夜培养贴壁后,加入梯度浓度的奥拉帕尼 (10µM~100µM)、尼拉帕尼 (10µM~100µM)或W18(0.10~1.0µM)单药,或W18与奥拉帕尼、W18与尼拉帕尼两药联合,每个药物浓度设3平行孔。继续培养72 h后,弃除培养液,每孔加入0.5mg/ml MTT 100µl(无血清的RPMI1640培养液溶解),继续培养4h后,弃除MTT,每孔加入DMSO 150µl,混和振荡5min,570nm波长处测定吸光度值,用如下公式计算细胞毒性(抑制率%):抑制率(%)=(1-药物处理细胞的OD值均值/对照细胞OD值均值)×100%,三次独立实验结果以均值±SD表示。
结果如表1和2所示,内在耐药的卵巢癌OVCAR5细胞对奥拉帕尼和尼拉帕尼敏感性较低,高浓度奥拉帕尼(10~100µM)或尼拉帕尼(10~100µM)单独作用时仍不能完全杀死治疗细胞。低浓度W18(0.10~1.0µM)单独作用对OVCAR5细胞的存活无显著影响,但与奥拉帕尼或尼拉帕尼联用能显著增强其对OVCAR5细胞的细胞毒作用(抗肿瘤活性),具有明显的协同增效的作用。
表1. W18单独或与奥拉帕尼联用对内在耐药卵巢癌OVCAR5细胞的细胞毒性
注:表1中,*P<0.05,**P<0.01vs.奥拉帕尼(10µM);# P<0.05,## P<0.01vs.奥拉帕尼(25µM);△ P<0.05,△△ P<0.01vs.奥拉帕尼(50µM);▽ P<0.05vs.奥拉帕尼(100µM)。
表2.W18单独或与尼拉帕尼联用对内在耐药卵巢癌OVCAR5细胞的细胞毒性
注:表2中,*P<0.05,**P<0.01vs.尼拉帕尼(10µM);# P<0.05,## P<0.01vs.尼拉帕尼(25µM);△ P<0.05,△△ P<0.01vs.尼拉帕尼(50µM);▽ P<0.05vs.尼拉帕尼(100µM)。
实施例2
W18联用奥拉帕尼或尼拉帕尼对获得性耐药卵巢癌A2780/R细胞毒性的协同增效作用
MTT法检测奥拉帕尼、尼拉帕尼单独或联用W18对获得性耐药卵巢癌A2780/R细胞的细胞毒性:5000个/孔的对数生长期的A2780/R细胞接种于96孔培养板内,过夜培养贴壁后,加入梯度浓度的奥拉帕尼 (10µM~100µM)、尼拉帕尼 (10µM~100µM)或W18(0.10~1.0µM)单药,或W18与奥拉帕尼、W18与尼拉帕尼两药联合,每个药物浓度设3平行孔。继续培养72h后,弃除培养液,每孔加入0.5mg/ml MTT 100µl(无血清的RPMI1640培养液溶解),继续培养4h后,弃除MTT,每孔加入DMSO 150µl,混和振荡5min,570nm波长处测定吸光度值,用如下公式计算细胞毒性(抑制率%):抑制率(%)=(1-药物处理细胞的OD值均值/对照细胞OD值均值)×100%,三次独立实验结果以均值±SD表示。
结果如表3和4所示,获得性耐药卵巢癌A2780/R细胞对奥拉帕尼和尼拉帕尼敏感性较低,高浓度奥拉帕尼(10~100 µM)或尼拉帕尼(10~100 µM)单独作用时仍不能完全杀死治疗细胞。低浓度W18(0.10~1.0 µM)单独作用对A2780/R细胞的存活无显著影响,但与奥拉帕尼或尼拉帕尼联用能显著增强其对A2780/R细胞的细胞毒作用(抗肿瘤活性),具有明显的协同增效的作用。
表3.W18单独或与奥拉帕尼联用获得性耐药卵巢癌A2780/R细胞的细胞毒性
注:表3中,*P<0.05,**P<0.01vs.奥拉帕尼(10µM);# P<0.05,## P<0.01vs.奥拉帕尼(25µM);△ P<0.05,△△ P<0.01vs.奥拉帕尼(50µM);▽ P<0.05,▽▽ P<0.01vs.奥拉帕尼(100µM)。
表4.W18单独或与尼拉帕尼联用获得性耐药卵巢癌A2780/R细胞的细胞毒性
注:表4中,*P<0.05,**P<0.01vs.尼拉帕尼(10µM);# P<0.05,## P<0.01vs.尼拉帕尼(25µM);△ P<0.05,△△ P<0.01vs.尼拉帕尼(50µM);▽ P<0.05,▽▽ P<0.01vs.尼拉帕尼(100µM)。
实施例3
W18与奥拉帕尼或尼拉帕尼联用对内在耐药卵巢癌OVCAR5细胞单细胞增殖、克隆形成能力抑制作用的影响
集落形成实验检测奥拉帕尼或尼拉帕尼单用或联用W18对内在耐药卵巢癌OVCAR5细胞单细胞增殖、克隆能力的影响:对指数生长期OVCAR5细胞悬液倍比稀释,按照每皿含200个细胞的浓度分别接种5ml细胞悬液到培养皿(直径60mm)中,十字方向轻轻晃动培养皿,使细胞分散均匀。培养皿置37℃、5%CO2培养24h 细胞贴壁后,加入奥拉帕尼(10~100µM)、尼拉帕尼(10~100µM)或W18(0.10~1.0µM)、或W18与奥拉帕尼、W18与尼拉帕尼两药联合,再培养2~3周,弃去培养液,PBS液小心浸洗2次,空气干燥。甲醇固定15min,弃甲醇后空气干燥。用Giemsa染液染色10min,流水缓慢洗去染液,空气干燥。显微镜下计数大于50个细胞克隆数,按下式计算集落形成率:集落形成率(%)=(集落数/接种细胞数)×100%,三次独立实验结果以均值±SD表示。
结果如表5和6所示,低浓度W18(0.10~1.0 µM)单独作用对OVCAR5细胞单细胞增殖、克隆能力(集落形成率%)无明显影响,无统计学差异;高浓度的奥拉帕尼(10~100 µM)或尼拉帕尼(10~100 µM)单独作用能浓度依赖性的抑制OVCAR5细胞集落形成率,但即使在100µM浓度下,仍不能完全抑制OVCAR5细胞的单细胞增殖、克隆形成,而低浓度W18与奥拉帕尼或尼拉帕尼联用后显著增强其对OVCAR5细胞单细胞增殖、克隆形成的抑制作用,具有协同增效的作用。
表5.W18与奥拉帕尼联用对OVCAR5细胞集落形成率(%)的影响
注:表5中,*P<0.05,**P<0.01vs.奥拉帕尼(10µM);# P<0.05,## P<0.01vs.奥拉帕尼(25µM);△ P<0.05,△△ P<0.01vs.奥拉帕尼(50µM);▽ P<0.05,▽▽ P<0.01vs.奥拉帕尼(100µM)。
表6.W18与尼拉帕尼联用对OVCAR5细胞集落形成率(%)的影响
注:表6中,*P<0.05,**P<0.01vs.尼拉帕尼(10µM);# P<0.05,## P<0.01vs.尼拉帕尼(25µM);△ P<0.05,△△ P<0.01vs.尼拉帕尼(50µM);▽ P<0.05,▽▽ P<0.01vs.尼拉帕尼(100µM)。
实施例4
W18与奥拉帕尼或尼拉帕尼联用对获得性耐药卵巢癌A2780/R细胞单细胞增殖、克隆形成能力抑制作用的影响
集落形成实验检测奥拉帕尼或尼拉帕尼单用或联用W18对获得性耐药卵巢癌A2780/R细胞单细胞增殖、克隆能力的影响:对指数生长期A2780/R细胞悬液倍比稀释,按照每皿含200个细胞的浓度分别接种5ml细胞悬液到培养皿(直径60mm)中,十字方向轻轻晃动培养皿,使细胞分散均匀。培养皿置 37℃、5%CO2培养24 h 细胞贴壁后,加入梯度浓度的奥拉帕尼 (10~100µM)、尼拉帕尼(10~100µM)或W8(0.10~1.0µM)、或W18与奥拉帕尼、W18与尼拉帕尼两药联合,再培养2~3周,弃去培养液,PBS液小心浸洗2次,空气干燥。甲醇固定15min,弃甲醇后空气干燥。用Giemsa染液染色10min,流水缓慢洗去染液,空气干燥。显微镜下计数大于50个细胞克隆数,按下式计算集落形成率:集落形成率(%)=(集落数/接种细胞数)×100%,三次独立实验结果以均值±SD表示。
结果如表7和8所示,低浓度W18(0.10~1.0 µM)单独作用对获得性耐药卵巢癌A2780/R细胞单细胞增殖、克隆能力(集落形成率%)无明显影响,无统计学差异;高浓度的奥拉帕尼(10~100 µM)或尼拉帕尼(10~100 µM)单独作用能浓度依赖性的抑制A2780/R细胞集落形成率,但即使在100µM浓度下,仍不能完全抑制A2780/R细胞的单细胞增殖、克隆形成,而低浓度W18与奥拉帕尼或尼拉帕尼联用后显著增强其对A2780/R细胞单细胞增殖、克隆形成的抑制作用,具有协同增效的作用。
表7.W18与奥拉帕尼联用对A2780/R细胞集落形成率(%)的影响
注:表7中,*P<0.05,**P<0.01vs.奥拉帕尼(10µM);# P<0.05,## P<0.01vs.奥拉帕尼(25µM);△ P<0.05,△△ P<0.01vs.奥拉帕尼(50µM);▽ P<0.05,▽▽ P<0.01vs.奥拉帕尼(100µM)。
表8.W18与尼拉帕尼联用对A2780/R细胞集落形成率(%)的影响
注:表8中,*P<0.05,**P<0.01vs.尼拉帕尼(10µM);# P<0.05,## P<0.01vs.尼拉帕尼(25µM);△ P<0.05,△△ P<0.01vs.尼拉帕尼(50µM);▽ P<0.05,▽▽ P<0.01vs.尼拉帕尼(100µM)。
Claims (8)
1.一种双去甲基汉防己甲素双甲酸乙酯与聚腺苷二磷酸核糖聚合酶-1抑制剂联合在制造治疗肿瘤药物的用途,所述聚腺苷二磷酸核糖聚合酶-1抑制剂为奥拉帕尼或尼拉帕尼,所述双去甲基汉防己甲素双甲酸乙酯的结构式为:
。
2.根据权利要求1所述的用途,所述肿瘤为耐药性肿瘤。
3.根据权利要求1所述的用途,所述联合是指不分先后间隔给药或同时给药,或以固定剂量形式给药。
4.根据权利要求1所述的用途,所述双去甲基汉防己甲素双甲酸乙酯与奥拉帕尼或尼拉帕尼的摩尔比为(0.10~1.0):(10~100)。
5.根据权利要求1或2所述的用途,其特征在于,所述肿瘤为卵巢癌。
6.一种用于治疗耐药性肿瘤的药物组合物,包含双去甲基汉防己甲素双甲酸乙酯、聚腺苷二磷酸核糖聚合酶-1抑制剂和药学上可接受的药用辅料,所述双去甲基汉防己甲素双甲酸乙酯的结构式如下:
。
7.根据权利要求6所述的药物组合物,其制剂形式为口服片剂、颗粒剂、胶囊、注射剂或复合包装。
8.根据权利要求6所述的药物组合物,所述肿瘤为耐药性卵巢癌。
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"H1, a derivative of tetrandrine, enhances the efficacy of 5-FU in Bel7402/5-FU cells via suppressing STAT3/MCL-1 and inducing PUMA";Fengli Li et al.;《Biochemical and Biophysical Research Communications》;第520卷;第93-98页 * |
"Synthesis, biological evaluation and toxicity of novel tetrandrine analogues";Ramona Schütz et al.;《European Journal of Medicinal Chemistry》;第207卷;第1-19页 * |
"汉防己甲素衍生物W6和W18逆转肿瘤多药耐药及BrTet增强Bel7402细胞凋亡敏感性的作用机制研究";刘小东;《CNKI博士学位论文全文库 医药卫生科技辑》(第9期);第1-125页 * |
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