CN115105599A - 一种抗肿瘤的联合用药物及其应用 - Google Patents
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Abstract
本发明公开了一种抗肿瘤的联合用药物及其应用。该抗肿瘤的联合用药物包括作为活性成分的细胞周期蛋白依赖性激酶抑制剂和铂类药物,所述的细胞周期蛋白依赖性激酶抑制剂为帕博西尼,瑞博西尼,玻玛西尼,奥罗莫星,阿特波龙和阿贝西尼中的至少一种。所述的铂类药物为顺铂,卡铂,奈达铂,奥沙利铂,乐铂和庚铂中的至少一种。具体地,将顺铂(或其他铂类药物)和帕博西尼(或其他细胞周期蛋白依赖性激酶抑制剂)联用治疗肿瘤可以产生明显的协同效应。本发明还对其协同的机制进行了研究,为肿瘤的有效治疗提供了新的策略。
Description
技术领域
本发明涉及一种细胞周期蛋白依赖性激酶抑制剂和铂类药物治疗癌症的联合用药物其应用,并对其联用机制进行了研究,属于医药技术领域。
背景技术
癌症有着较高的发病率和致死率,是严重危害人类健康的主要疾病之一,据世界卫生组织预计,在2030年,每年将会约有2200万新增病例和1300万人因癌症或癌症相关并发症死亡。因此如何治疗癌症一直是全世界共同的研究方向。虽然近年来对于癌症的研究颇多,也取得了许多进步,但由于癌症极快的发生发展率,如何有效抑制肿瘤生长仍是亟待解决的问题。
联合用药是为了达到治疗目的而采用的两种或两种以上药物同时或先后应用,其具有发挥药物的协同治疗作用以提高疗效、延迟或减少耐药性的发生、减少给药剂量从而降低毒副反应的优点。因此目前临床上较少单独应用一种化疗药物进行治疗,大多是联合药物进行治疗以期实现更强的抗肿瘤效果,更弱的副作用。
细胞周期蛋白依赖性激酶(CDK)是丝氨酸/苏氨酸蛋白激酶家族成员,在细胞的周期循环中起到至关重要的作用。细胞周期素依赖激酶4/6(CDK4/6)能和细胞周期蛋白D(cyclinD)组装形成复合物,促使视网膜母细胞瘤蛋白(Rb)磷酸化继而推动细胞进入细胞周期进行分裂增殖。细胞周期蛋白依赖性激酶抑制剂如帕博西尼,瑞博西尼,玻玛西尼,奥罗莫星,阿特波龙和阿贝西尼等是目前常用的细胞周期素依赖激酶4/6(CDK4/6)的抑制剂,能阻断视网膜母细胞瘤蛋白的磷酸化,近来已逐渐成为治疗视网膜母细胞瘤蛋白(Rb)阳性肿瘤的重要药物。细胞周期素依赖激酶同样也与细胞内代谢途径息息相关,有研究报道CDK4/6抑制剂在阻断相关蛋白磷酸化的同时也会导致戊糖磷酸途径和丝氨酸合成途径受阻,从而导致细胞内活性氧含量增加。有文献报道细胞内活性氧含量能够增强化疗药物对肿瘤细胞的杀伤作用,但目前利用CDK4/6抑制剂引起细胞内活性氧增加从而增敏化疗药物的研究未见报道。此外,CDK4/6抑制剂单独使用时仅能可逆地阻滞细胞周期并不能有效诱导肿瘤细胞凋亡,一旦停药,肿瘤细胞会迅速增殖导致肿瘤复发。
自1978年美国食品与药品监督管理局批准,顺铂作为首个上市的铂类抗肿瘤药物因其抗肿瘤活性强,抗肿瘤谱广,一直是临床上广泛运用的抗肿瘤药物。顺铂及其衍生物能够嵌入双股DNA分子中,诱导肿瘤细胞发生凋亡。但铂类抗肿瘤药物单独应用时易导致肿瘤耐药的产生且会引起诸多副作用,如肾脏损伤和骨髓抑制等。因此,提高铂类药物对肿瘤的疗效,减少使用剂量、减弱副作用及扩大铂类药物在肿瘤治疗中的应用范围具有重要的应用前景。有研究表明,当肿瘤细胞处在高ROS浓度的环境时对铂类抗肿瘤药物的敏感性会显著增加。但铂类抗肿瘤药物联用CDK4/6抑制剂是否具有协同抗肿瘤作用仍有待进一步研究。
发明内容
CDK4/6抑制剂,近来已成为视网膜母细胞瘤蛋白(Rb)阳性癌症如乳腺癌,尤其是雌激素受体阳性乳腺癌的明星药物。但其不能有效诱导肿瘤细胞凋亡,一旦停止治疗,肿瘤会迅速复发。为了解决这一问题,本发明人创造性地利用帕博西尼能导致肿瘤内活性氧(ROS)水平显著增加的特性,联用了细胞毒性的铂类药物。该联用方案中CDK4/6抑制剂能通过促进ROS产生来增强癌细胞的化疗敏感性,从而增加铂类药物的肿瘤杀伤能力,两种药物联用后可以产生较好的协同效应,显著提高抗肿瘤效果。
本发明的目的之一在于克服现有CDK4/6抑制剂的缺点和不足,结合细胞毒性的铂类药物,提供一种可有效杀伤肿瘤细胞的联合用药物。
本发明的目的通过下述技术方案实现:一种抗肿瘤的联合用药物,包括作为活性成分的CDK4/6抑制剂和细胞毒性的铂类药物。
所述的铂类药物为顺铂,卡铂,奈达铂,奥沙利铂,乐铂和庚铂中的至少一种;优选为顺铂。
所述的细胞周期蛋白依赖性激酶抑制剂为帕博西尼,瑞博西尼,玻玛西尼,奥罗莫星,阿特波龙和阿贝西尼中的至少一种;优选为帕博西尼。
所述的肿瘤包括三阴性乳腺癌、恶性黑色素瘤,肝癌,肺癌,结肠癌,鼻咽癌,膀胱癌,宫颈癌,食管癌,胃癌,前列腺癌和淋巴瘤;优选为三阴性乳腺癌。
所述的CDK4/6抑制剂的有效浓度是0.025~100μg/ml,细胞毒性的铂类药物有效浓度是0.1~200μg/ml。
本发明是将CDK4/6抑制剂和细胞毒性的铂类药物同时加至肿瘤细胞中,或先用CDK4/6抑制剂处理肿瘤再加入细胞毒性的铂类药物,或者先用细胞毒性的铂类药物处理肿瘤细胞再加入CDK4/6抑制剂。
本发明所述的CDK4/6抑制剂和细胞毒性的铂类药物的联合用药物可有效地诱导肿瘤细胞凋亡,从而抑制乳腺癌的进展。
本发明所述的CDK4/6抑制剂可显著地引起肿瘤细胞ROS水平升高和线粒体膜电位下降,从而增敏细胞毒性的铂类药物。
本发明所述的CDK4/6抑制剂和细胞毒性的铂类药物的联合用药物最佳的摩尔比为1:2。
本发明所述的CDK4/6抑制剂和细胞毒性的铂类药物的联合用药物可显著地抑制体内肿瘤的生长。
本发明相对于现有技术具有如下的优点及效果:
1.本发明提供一种联合用药物治疗肿瘤的方法,涉及CDK4/6抑制剂和铂类药物,二者联合用药可有效地诱导肿瘤细胞凋亡,从而抑制肿瘤的进展。
2.本发明对CDK4/6抑制剂和铂类药物联合用药的协同机制进行了研究。具体的,细胞周期蛋白依赖性激酶抑制剂可显著地引起肿瘤细胞ROS水平升高和膜电位下降,从而增敏细胞毒性的铂类药物并且这两种药物的组合可以产生较好的针对三阴性乳腺癌的协同治疗效果。因此该项技术具有巨大的经济价值与社会意义。
3.通过Chou-Talalay方法分析了CDK4/6抑制剂和细胞毒性铂类药物的协同指数,得出联合用药物最佳的摩尔比为1:2。
附图说明:
以下,结合附图来详细说明本发明的实施方案,其中:
图1表示顺铂和帕博西尼对人三阴性乳腺癌MDA-MB-231细胞的细胞毒性图。
图2表示流式细胞术检测顺铂和帕博西尼对人三阴性乳腺癌MDA-MB-231细胞凋亡的影响图。
图3表示流式细胞术检测顺铂和帕博西尼对人三阴性乳腺癌MDA-MB-231细胞ROS水平的影响图。
图4表示流式细胞术检测顺铂和帕博西尼对人三阴性乳腺癌MDA-MB-231细胞线粒体膜电位的影响图。
图5表示不同比例顺铂和帕博西尼对人三阴性乳腺癌MDA-MB-231细胞的协同指数图。
图6表示顺铂和帕博西尼联用策略对小鼠原位瘤的生长影响情况图。
具体实施方式:
下面结合实施例对本发明作进一步详细的描述,但本发明的实施方式不限于此。下面参照实施例进一步详细阐述本发明,但是本领域技术人员应当理解,本发明并不局限于这些实施例以及使用的制备方法。而且,本领域技术人员根据本发明的描述可以对本发明进行等同替换,组合,改良或修饰,但这些都将包括在本发明的范围内。
实施例1帕博西尼增敏顺铂对MDA-MB-231细胞的细胞毒性
取对数生长期的MDA-MB-231细胞,计数后调整细胞悬液密度,以5×103cells/孔的密度接种于96孔细胞培养板,在培养箱中培养24h。分为对照组,顺铂组,帕博西尼组和顺铂+帕博西尼组进行试验:
对照组:加入200μl RPMI1640培养基(含10%FBS);
帕博西尼组:加入200μl含1μg/ml帕博西尼的RPMI1640培养基(含10%FBS);
在37℃5%CO2孵箱中孵育48h后,弃去含药培养基每孔换用200μl新鲜培养基继续孵育24h。然后每孔加入20μL浓度为5mg/mL的MTT溶液,继续孵育4h,吸出上清并加入150μLDMSO,于37℃摇床振荡30min,使蓝紫色结晶充分溶解,采用酶标仪在570nm波长处测定吸光度值。采用以下公式计算相对抑制率(RIR):RIR(%)=[1-(Ce-C0)/(Cc-C0)]×100%(Ce:实验组吸光度;C0:空白组吸光度;Cc:对照组吸光度)。给药后24h的半数抑制浓度(IC50)使用SPSS软件拟合计算得到。
由图1可见,帕博西尼在较高浓度(1μg/ml)下无法引起MDA-MB-231细胞的死亡,而单独的顺铂则表现出剂量依赖性的细胞毒性,IC50为3.29±0.2μg/ml。与此同时,1μg/ml帕博西尼和顺铂联用时,顺铂的细胞毒性可以进一步提高,IC50为2.44±0.1μg/ml,这表明帕博西尼可以增敏顺铂。
实施例2流式细胞术检测顺铂和帕博西尼对MDA-MB-231细胞凋亡的影响
取对数生长期MDA-MB-231细胞,用胰蛋白酶消化后加培养基吹散成单细胞悬液。计数后,将细胞悬液稀释并以1×105cells/孔接种于12孔细胞培养板孵育过夜,吸弃旧培养基。分为对照组,顺铂组,帕博西尼组和顺铂+帕博西尼组进行试验:
对照组:加入2ml RPMI1640培养基(含10%FBS);
顺铂组:加入2ml含5μg/mL顺铂的RPMI1640培养基(含10%FBS);
帕博西尼组:加入2ml含2.5μg/ml帕博西尼的RPMI1640培养基(含10%FBS);
顺铂+帕博西尼组:加入2ml含5μg/mL顺铂和2.5μg/ml帕博西尼的RPMI1640培养基(含10%FBS);
孵育48h后,收集上清中的细胞,再用0.25%胰酶消化并收集贴壁的MDA-MB-231细胞,合并两部分细胞。离心收集细胞,PBS洗3次,用100μLPBS将细胞分散均匀,按照AnnexinV-FITC/7-AAD凋亡双染试剂盒说明书进行染色,用流式细胞仪进行检测。结果如说明书附图图2所示。
由图2可见,对照组和帕博西尼的凋亡细胞比例较少,帕博西尼组中仅观察到8.2%的早期凋亡细胞和3.3%的晚期凋亡细胞和死亡细胞。细胞毒性的顺铂则诱导了更多的细胞凋亡(22.5%的早期凋亡细胞和8.4%的晚期凋亡细胞);而帕博西尼和顺铂联用组则显示出最高的细胞凋亡诱导作用(早期凋亡细胞占30.4%,晚期凋亡细胞占24.9%),再次表明帕博西尼可以增敏顺铂,增强抗肿瘤效果。
实施例3流式细胞术检测帕博西尼对MDA-MB-231细胞ROS水平的影响
取对数生长期MDA-MB-231细胞,用胰蛋白酶消化后加培养基吹散成单细胞悬液。计数后,将细胞悬液稀释并以1×105cells/孔接种于12孔板,孵育过夜。分为对照组,顺铂组,帕博西尼组和顺铂+帕博西尼组进行试验:
对照组:加入2ml RPMI1640培养基(含10%FBS);
顺铂组:加入2ml含5μg/mL顺铂的RPMI1640培养基(含10%FBS);
帕博西尼组:加入2ml含2.5μg/ml帕博西尼的RPMI1640培养基(含10%FBS);
顺铂+帕博西尼组:加入2ml含5μg/mL顺铂和2.5μg/ml帕博西尼的RPMI1640培养基(含10%FBS);
孵育24h后,收集上清中的细胞,再用0.25%胰酶消化并收集贴壁的MDA-MB-231细胞,合并两部分细胞。离心收集细胞,PBS洗3次,根据活性氧检测试剂盒的操作方法进行后续处理,加入2',7'-二氯荧光黄双乙酸盐(DCFH-DA)(10μM)溶液,于37℃孵育25min,PBS洗3次,通过流式细胞仪定量测定细胞中2',7'-二氯荧光素(DCF)的荧光强度。结果如说明书附图图3所示。
由图3可见,与对照组相比,帕博西尼和顺铂均能引起MDA-MB-231细胞ROS水平一定程度的增加,而帕博西尼顺铂联用组则能够诱导产生最高的细胞内ROS水平。
实施例4流式细胞术检测帕博西尼对MDA-MB-231细胞线粒体膜电位的影响
取对数生长期MDA-MB-231细胞,用胰蛋白酶消化后加培养基吹散成单细胞悬液。计数后,将细胞悬液稀释并以5×105cells/孔接种于12孔板,孵育过夜。分为对照组,顺铂组,帕博西尼组和顺铂+帕博西尼组进行试验:
对照组:加入2ml RPMI1640培养基(含10%FBS);
顺铂组:加入2ml含5μg/mL顺铂的RPMI1640培养基(含10%FBS);
帕博西尼组:加入2ml含2.5μg/ml帕博西尼的RPMI1640培养基(含10%FBS);
顺铂+帕博西尼组:加入2ml含5μg/mL顺铂和2.5μg/ml帕博西尼的RPMI1640培养基(含10%FBS);孵育24h后,收集上清中的细胞,再用0.25%胰酶消化并收集贴壁的MDA-MB-231细胞,合并两部分细胞。离心收集细胞,PBS洗3次,重悬于0.5ml培养液中,根据线粒体膜电位检测试剂盒的方法配置JC-1染色工作液,每管加入0.5ml JC-1染色工作液,吹匀,37℃孵育30min。孵育结束后,离心收集细胞,弃上清,分散于1ml JC-1染色缓冲液(1×),JC-1染色缓冲液(1×)是用JC-1染色缓冲液(5×)用纯水稀释后得到。离心收集细胞,在重分散于0.5JC-1染色缓冲液(1×)通过流式细胞仪进行测定。
由图4可见,与对照组相比,在给予顺铂后会仅能较小程度地降低线粒体的细胞膜电位,而在给与帕博西尼后,会引起更强的线粒体膜电位的降低,顺铂帕博西尼两者联用则能够最大程度地降低线粒体膜电位。
实施例5不同比例顺铂和帕博西尼联用的筛选和协同指数的计算
取对数生长期的MDA-MB-231细胞,计数后调整细胞悬液密度,以5×103cells/孔的密度接种于96孔细胞培养板,在培养箱中培养24h。分为对照组,顺铂组,帕博西尼组和顺铂+帕博西尼组进行试验:
对照组:加入200μl RPMI1640培养基(含10%FBS);
顺铂组:加入200μl最高含2.5μg/ml顺铂(按照等倍稀释制备系列低浓度含药培养基)的RPMI1640培养基(含10%FBS);
帕博西尼组:加入200μl含有与上述顺铂不同摩尔比1:0.3、1:0.5、1:1、1:2、1:4的帕博西尼的RPMI1640培养基(含10%FBS);
顺铂+帕博西尼组:加入200μl最高含2.5μg/ml顺铂(按照等倍稀释制备系列低浓度含药培养基)和不同摩尔比1:0.3、1:0.5、1:1、1:2、1:4帕博西尼的RPMI1640培养基(含10%FBS);
在37℃5%CO2孵箱中分别培养48h后,弃去含药培养基每孔换用200μl新鲜培养基继续孵育24h。然后每孔加入20μl浓度为5mg/ml的MTT溶液,继续孵育4h,吸出上清并加入150μl DMSO,于37℃摇床振荡30min,使蓝紫色结晶充分溶解,采用酶标仪在570nm波长处测定吸光度值。采用以下公式计算相对抑制率(RIR):RIR(%)=[1-(Ce-C0)/(Cc-C0)]×100%(Ce:实验组吸光度;C0:空白组吸光度;Cc:对照组吸光度)。在联合用药物疗法中,两药摩尔比的变化可引起药物协同或拮抗的相互作用的变化。为了进一步优化顺铂和帕博西尼在联合给药中的摩尔比,本部分通过CompuSyn软件按照Chou-Talalay的方法评价分析了不同比例下顺铂帕博西尼的给药效果。计算得到不同程度生长抑制(Fa,受影响细胞比例)下两者的协同指数(CI,CI<0.9表示协同作用;CI>1.1表示拮抗作用;0.9<CI<1.1,表示加和作用)。
由图5可见,在不同比例下,顺铂和帕博西尼均表现出协同抗肿瘤作用且在Fa为75%时,1:2组的协同指数低于其他各组,这表明1:2组的协同作用强于其他组。因此,在后面的研究中将1:2这一摩尔比定义为最佳的联合用药比例。
实施例6顺铂帕博西尼联用策略对小鼠原位瘤的生长影响情况
取对数生长期MDA-MB-231细胞,用胰蛋白酶消化后加培养基吹散成单细胞悬液。计数后,将细胞悬液稀释至3×106cells/ml,每只小鼠(裸鼠,BALB/c,雌性,购于四川成都达硕生物科技有限公司)接种100μl细胞悬液至右侧第三对乳腺垫,建立MDA-MB-231原位瘤小鼠模型。小鼠肿瘤生长监测通过游标卡尺测量肿瘤长径(a)和短径(b),肿瘤的体积(V),公式为:V=a×b2/2计算。待肿瘤生长至100mm3左右时,将动物随机分成4组,每组5只,同时开始给药。开始给药当天定义为第0天,每间隔2天通过尾静脉注射给药,共给药2次。每两天测量肿瘤大小。
给药方法:
1)对照组:通过尾静脉注射50μl生理盐水两次;
2)顺铂组:通过尾静脉注射50μl生理盐水(含顺铂5mg/kg)两次;
3)帕博西尼组:通过尾静脉注射50μl生理盐水(含帕博西尼14.8mg/kg)两次;
4)帕博西尼联合顺铂组:通过尾静脉注射50μl生理盐水(含顺铂5mg/kg和帕博西尼6.4mg/kg)两次;实验结束时处死小鼠,记录原位肿瘤体积生长曲线,结果如图6所示。
结果表明帕博西尼或顺铂单独使用,两者都不能有效地抑制原位肿瘤的生长(肿瘤抑制率:顺铂,31.5%;帕博西尼20.5%),而两药联用组具有最强的抑制原位肿瘤生长的作用(肿瘤抑制率:57.4%)。说明顺铂帕博西尼联用这一策略能够利用帕博西尼增敏顺铂,放大顺铂的细胞毒性作用,两者协同抑制肿瘤就能更有效地抑制原位肿瘤的生长。这为协同治疗肿瘤提供了一种新的方法。
Claims (9)
1.一种增强抗肿瘤效果的联合用药物,其特征在于:包括作为活性成分的细胞周期蛋白依赖性激酶抑制剂和细胞毒性的铂类药物,所述联合用药物应用于抗肿瘤治疗。
2.根据权利要求1中所述的增强抗肿瘤效果的联合用药物,其特征在于:所述的细胞周期蛋白依赖性激酶抑制剂为帕博西尼,瑞博西尼,玻玛西尼,奥罗莫星,阿特波龙和阿贝西尼中的至少一种。
3.根据权利要求1中所述的增强抗肿瘤效果的联合用药物,其特征在于:所述的细胞毒性的铂类药物为顺铂,卡铂,奈达铂,奥沙利铂,乐铂和庚铂中的至少一种。
4.根据权利要求3中所述的增强抗肿瘤效果的联合用药物,其特征在于:所述的细胞周期蛋白依赖性激酶抑制剂为帕博西尼。
5.根据权利要求1中所述的增强抗肿瘤效果的联合用药物,其特征在于:所述的肿瘤包括乳腺癌,恶性黑色素瘤,肝癌,肺癌,结肠癌,鼻咽癌,膀胱癌,宫颈癌,食管癌,胃癌,前列腺癌和淋巴瘤。
6.根据权利要求1中所述的增强抗肿瘤效果的联合用药物,其特征在于:作为活性成分的细胞周期蛋白依赖性激酶抑制剂和细胞毒性的铂类药物的摩尔比为1:0.3~1:4。
7.细胞周期蛋白依赖性激酶抑制剂和细胞毒性的铂类药物在制备抗肿瘤药物中的应用。
8.根据权利要求7中所述的应用,其特征在于:所述的细胞周期蛋白依赖性激酶抑制剂为帕博西尼,瑞博西尼,玻玛西尼,奥罗莫星,阿特波龙和阿贝西尼中的至少一种。
9.根据权利要求7中所述的应用,其特征在于:所述的细胞毒性的铂类药物为顺铂,卡铂,奈达铂,奥沙利铂,乐铂和庚铂中的至少一种。
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