CN110433290A - 隐丹参酮和TKI抑制剂联用在制备Ph+急性淋巴细胞白血病化疗药物中的应用 - Google Patents
隐丹参酮和TKI抑制剂联用在制备Ph+急性淋巴细胞白血病化疗药物中的应用 Download PDFInfo
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- CN110433290A CN110433290A CN201910766099.9A CN201910766099A CN110433290A CN 110433290 A CN110433290 A CN 110433290A CN 201910766099 A CN201910766099 A CN 201910766099A CN 110433290 A CN110433290 A CN 110433290A
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- cryptotanshinone
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- lymphoblastic leukemia
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Abstract
本发明公开了隐丹参酮和TKI抑制剂联用在制备急性淋巴细胞白血病的治疗和/或预防药物、耐药逆转药物和/或预后防复发的药物中的应用。本发明研究发现,将隐丹参酮和抗癌药物TKI抑制剂配伍联用时,隐丹参酮可以大大增加白血病细胞对抗癌药物的敏感性,爆发式提高多种抗癌药物对急性淋巴细胞白血病细胞的增殖抑制效果,从而使各药物的使用量远低于当前临床的药物使用量,并实现爆发式协同增效的作用。因此,本发明中隐丹参酮作为有效的急性淋巴细胞白血病的化疗增敏药物,在治疗急性淋巴细胞白血病和解决急性淋巴细胞白血病耐药问题方面具有重要研究意义和广泛的应用前景。
Description
技术领域
本发明属于生物医药技术领域,更具体地,涉及隐丹参酮和TKI抑制剂联用在制备Ph+急性淋巴细胞白血病化疗药物中的应用。
背景技术
白血病俗称“血癌”,是一类来源于造血干细胞的恶性血液肿瘤疾病,分为淋巴细胞白血病和髓细胞性白血病。淋巴细胞白血病分为急性淋巴细胞白血病(ALL)和慢性淋巴细胞白血病(CLL),其中,Ph+急性淋巴细胞白血病(Ph+ALL)的病程进展迅速、恶性程度高、预后极差。针对靶向费城染色体(Philadelphia,Ph)的药物-TKI抑制剂(如伊马替尼)等,患者在初期服用时的疗效良好,但疗效有限,同时很快便会出现耐药现象。
针对上述情况,在临床治疗Ph+急性淋巴细胞白血病时,往往选用将TKI抑制剂(如伊马替尼)与广谱的细胞毒性化疗药物(如:环磷酰胺、氨甲喋呤等)进行联合使用,以增强药物疗效、推迟耐药现象。然而,上述疗法在应用中也存在很大的问题:首先,以细胞周期阻滞药为主的常用化疗方案虽然阻止了白血病细胞的异常增殖,但也严重阻碍了正常机体细胞的分裂;第二,化疗药物代谢过程复杂,对患者的心、肝、肾等重要器官损伤严重;第三,常用化疗虽能迅速缓解疾病,但极易产生耐药和复发。
而天然化合物以其疗效显著、廉价易得、毒副作用低等优势吸引着人们的目光,将能够增加细胞化疗敏感性的天然化合物与现有抗癌药物进行联合使用,不仅可大大减低药物的使用量、降低毒副作用,还可以延缓甚至避免耐药现象的发生。因此,在Ph+急性淋巴细胞白血病治疗领域,亟需开发一种能够大大增强Ph+急性淋巴细胞白血病细胞化疗敏感性、逆转对抗癌药物的耐药性、且毒副作用较小的天然药物。
发明内容
本发明要解决的技术问题是克服上述现有技术的缺陷和不足,提供隐丹参酮和TKI抑制剂联用在制备Ph+急性淋巴细胞白血病化疗药物中的应用。本发明研究发现,隐丹参酮(Cryptotanshinone,简称CPT)能够与抗癌药物(TKI抑制剂)联合配伍使用,引发爆发式的协同增效效果。如伊马替尼(Imatinib,简称IM),本发明研究发现隐丹参酮与以伊马替尼为代表的TKI抑制剂配伍使用,可以大大增加白血病细胞对抗癌药物的敏感性,可以爆发式提高多种抗癌药物对急性淋巴细胞白血病细胞的增殖抑制效果,实现协同增效的作用,从而使各药物的使用量远低于当前临床的药物使用量,达到低剂量、高效率杀死Ph+急性淋巴细胞白血病细胞的效果。同时,由于来自中草药的天然化合物隐丹参酮低毒且来源丰富、材料易得,能够大大减少治疗过程中药物对机体的毒副作用,并显著降低治疗成本。因此,隐丹参酮联合TKI抑制剂有望开发成为针对Ph+急性淋巴细胞白血病的化疗药物或化疗增敏药物应用于临床;同时,隐丹参酮联合TKI抑制剂的药物组合物也可应用于制备Ph+急性淋巴细胞白血病的治疗和/或预防药物、Ph+急性淋巴细胞白血病耐药逆转药物和/或预后防复发的药物、提高机体免疫力的药物中,以及应用于Ph+急性淋巴细胞白血病临床和基础的相关研究中。
本发明的第一个目的是提供隐丹参酮和抗癌药物联用在制备急性淋巴细胞白血病的治疗和/或预防药物中的应用。
本发明的第二个目的是提供隐丹参酮和抗癌药物联用在制备急性淋巴细胞白血病耐药逆转药物和/或预后防复发的药物中的应用。
本发明的第三个目的是提供一种急性淋巴细胞白血病的治疗药物。
本发明上述目的通过以下技术方案实现:
本发明研究发现,极微量(大于或等于1nmol/L)的隐丹参酮与抗癌药物联合使用时,可使隐丹参酮自身以及联用的抗癌药物用量大幅度下降,远远低于其单独使用的IC50浓度(细胞增殖的半数抑制浓度),且使急性淋巴细胞白血病细胞增殖的抑制率达到76%以上,引发爆发式的协同增效效果。其中,隐丹参酮有效的作用浓度为大于或等于1nmol/L。通过研究,我们发现隐丹参酮联合TKI抑制剂的药物组合物是一种很好的Ph+急性淋巴细胞白血病化疗药物或化疗增敏药物,可用于有效治疗Ph+急性淋巴细胞白血病、大幅增加Ph+急性淋巴细胞白血病细胞对抗癌药物的药物敏感性;采用隐丹参酮与抗癌药物联合使用应用于制备Ph+急性淋巴细胞白血病化疗药物或化疗增敏药物,可以解决由于药物不敏感或药物耐受、复发导致的疗效差或治疗失败的问题。其中,由于TKI抑制剂(如:伊马替尼等)为现有已临床应用的药物,隐丹参酮与TKI抑制剂(如:伊马替尼)的联合用药方式可迅速在临床治疗急性淋巴细胞白血病中成熟应用,无需再经过漫长的临床阶段,应用前景非常好。
因此,以下内容均应在本发明的保护范围之内:
本发明提供了隐丹参酮和抗癌药物联用在制备急性淋巴细胞白血病的治疗和/或预防药物中的应用;所述隐丹参酮包括隐丹参酮、其可药用的盐或酯、其衍生物、其衍生物在药学上可接受的盐、其衍生物的纳米级物质中的一种或几种的组合。
本发明还提供了隐丹参酮和抗癌药物联用在制备急性淋巴细胞白血病耐药逆转药物和/或预后防复发的药物中的应用;所述隐丹参酮包括隐丹参酮、其可药用的盐或酯、其衍生物、其衍生物在药学上可接受的盐、其衍生物的纳米级物质中的一种或几种的组合。
本发明提供的隐丹参酮和抗癌药物(TKI抑制剂)的联用,不论是作为急性淋巴细胞白血病治疗和/或预防药物组合物,还是急性淋巴细胞白血病耐药逆转药物和/或预后防复发药物组合物,均可以与其他抗癌药物二次联用,以期达到更优或毒副作用更小的治疗效果,且本领域常规的抗癌药物均可用于本发明中提到的二次联用中。
所述抗癌药物可以为天然抗癌药物也可以为人工合成的抗癌药物,包括但不限于抗癌化疗药物、抗炎类药物、免疫刺激剂、激素类药物或小分子靶向药物中的一种或几种的组合。
所述抗癌药物包括但不限于抗体药物、抗肿瘤中药复方制剂、抗肿瘤中药提取物或中药单体及其衍生物中的一种或几种的组合。
具体优选地,所述抗癌药物为TKI抑制剂;所述TKI抑制剂包括TKI抑制剂、其可药用的盐或酯、其衍生物、其衍生物在药学上可接受的盐、其衍生物的纳米级物质中的一种或几种的组合。
优选地,所述TKI抑制剂为伊马替尼、达沙替尼、尼洛替尼或普纳替尼(ponatinib)中的一种或几种的组合。
上述药物具有高效低毒的优点。
优选地,所述隐丹参酮和抗癌药物联用的比例为0.001~100:1。
更优选地,所述隐丹参酮和抗癌药物联用的比例为0.005~100:1。
更进一步优选地,所述隐丹参酮和抗癌药物联用的比例为0.01~100:1。
再进一步优选地,所述隐丹参酮和抗癌药物联用的比例为0.02~100:1。
在上述联合配伍方案中起减毒增效作用的活性成分为隐丹参酮。
研究结果显示,当隐丹参酮大于等于20nmol/L时,隐丹参酮与TKI抑制剂(如伊马替尼)配伍的药物组合物,对Ph+急性淋巴细胞白血病细胞的增殖抑制率可高达76%以上;上述隐丹参酮和抗癌药物配伍方式的使用量远远低于当前临床的使用量,不属于能够对机体造成伤害的范围。
本发明还提供了一种急性淋巴细胞白血病的治疗药物,包含有效量的隐丹参酮和抗癌药物;所述隐丹参酮包括隐丹参酮、其可药用的盐或酯、其衍生物、其衍生物在药学上可接受的盐、其衍生物的纳米级物质中的一种或几种的组合。
优选地,所述抗癌药物为TKI抑制剂;所述TKI抑制剂包括TKI抑制剂、其可药用的盐或酯、其衍生物、其衍生物在药学上可接受的盐、其衍生物的纳米级物质中的一种或几种的组合。
优选地,所述TKI抑制剂为伊马替尼、达沙替尼、尼洛替尼或普纳替尼(ponatinib)中的一种或几种的组合。
从另一个角度看,所述与隐丹参酮和抗癌药物(TKI抑制剂)组成的化疗药物组合物二次联用的抗癌药物,可以为天然抗癌药物也可以为人工合成的抗癌药物,包括但不限于抗癌化疗药物、抗炎类药物、免疫刺激剂、激素类药物或小分子靶向药物中的一种或几种的组合。
所述抗癌药物包括但不限于抗体药物、抗肿瘤中药复方制剂、抗肿瘤中药提取物或中药单体及其衍生物中的一种或几种的组合。
具体优选地,所述抗癌化疗药物可以为(但不限于)以下的一种或多种:足叶乙苷、5-氟尿嘧啶、环磷酰胺、阿霉素、柔红霉素、表柔比星、阿糖胞苷、靛红、顺铂、卡铂、依托泊苷、拓扑替康、伊立替康等等。
所述抗炎类药物可以为(但不限于)以下的一种或多种:阿司匹林、舒林酸、托美汀、吲哚美辛等等。
所述免疫刺激剂可以为(但不限于)以下的一种或多种:干扰素、环磷酸腺苷(c-AMP)、球蛋白等等。
所述激素类药物可以为(但不限于)以下的一种或多种:糖皮质激素、雌激素、孕激素等等。
所述小分子靶向药物可以为(但不限于)以下的一种或多种:伊马替尼(Imatinib)、达沙替尼(Dasatinib)、尼罗替尼(Nilotinib)、博舒替尼(Bosutinib)、舒尼替尼(Sutent,Sunitinib)、索拉非尼(Nexavar,Sorafenib)、拉帕替尼(Lapatinib)、易瑞沙(Gefitinib)等等。
所述抗体药物可以为(但不限于)以下的一种或多种:美罗华(Rituximab,Rituxan)、贺赛汀(Trastuzumab,Herceptin)、爱必妥(Cetuximab,Erbitux)、贝伐单抗(Bevacizumab,Avastin)、帕尼单抗(Panitumumab)、尼妥珠单抗(Nimotuzumab)等等。
所述抗肿瘤中药复方制剂可以为(但不限于)以下的一种或多种:砷靛参、枫苓合剂、蟾酥灵等等。
所述抗肿瘤中药提取物可以为(但不限于)以下的一种或多种:灵芝提取物、云芝提取物、茯苓提取物、薏苡仁提取物等等。
所述中药单体及其衍生物可以为(但不限于)以下的一种或多种:紫杉醇、喜树碱、高三尖杉酯碱、大豆异黄酮、人参皂苷、长春新碱、秋水仙碱、柚皮素、大黄素、苦参碱、葫芦素、乌头原碱、黄芩素、黄连素、姜黄素、青蒿素、雷公藤甲素以及上述所有单体的衍生物等等。
优选地,所述药物为口服制剂或注射制剂。
进一步地,所述药物还可包括可接受的药用载体和/或药学上可接受的赋形剂;可制成各种药学上可接受的制剂,包括片剂(控释片、缓释片)、颗粒剂、胶囊剂(硬胶囊、软胶囊)、丸剂、汤剂等口服制剂,冻干粉针制剂等注射剂。
优选地,所述药用载体包括(但并不限于)以下的一种或多种:盐水、缓冲液、葡萄糖、水、甘油、乙醇、低分子量右旋糖酐、聚乙二醇400、聚乙二醇6000、甘露醇、乳糖、葡萄糖、蔗糖、氯化钠、山梨醇。
本发明隐丹参酮和抗癌药物配伍组成的药物的制备方法不做严格限制。在无菌条件下,可制成针剂,例如用生理盐水或含有葡萄糖和其他辅剂的水溶液通过常规方法制备得到;可制成片剂和胶囊剂,通过常规方法制备得到。
针对急性淋巴细胞白血病细胞对抗癌药物不敏感、极易耐药且易复发的问题,本发明提出了将毒副作用较小的中草药有效成分隐丹参酮与抗癌药物(TKI抑制剂)用于制备急性淋巴细胞白血病化疗药物或化疗增敏药物,具体是将隐丹参酮与TKI抑制剂(如伊马替尼)抗癌药物进行配伍的联合用药,并给出了具体的配伍比例和相应剂量下细胞增殖的抑制情况。本发明研究发现该配伍方式能够极大地提高抗癌药物对急性淋巴细胞白血病细胞的增殖抑制效果,在隐丹参酮参与作用下,细胞增殖率呈爆发式下降。
另外,本发明提供的隐丹参酮和抗癌药物联用在制备预防急性淋巴细胞白血病的药物、提高机体免疫力的药物、保健药品或保健食品中的应用;在增敏和/或杀死急性淋巴细胞白血病细胞的分析试剂、生化试剂、检测试剂中的应用;在药效检测评估及相关药理、药效和临床研究中的应用;在细胞生物学、分子生物学、医学等相关学科的基础研究中的应用,均应在本发明的保护范围之内。
本发明中,优选地,所述急性淋巴细胞白血病为Ph+急性淋巴细胞白血病。
更优选地,所述Ph+急性淋巴细胞白血病为包含BCR-ABL融合蛋白基因的急性淋巴白血病。
更进一步优选地,所述包含BCR-ABL融合蛋白基因的急性淋巴白血病为Ph+急性淋巴细胞白血病细胞株Sup-B15细胞。
本发明中,所述TKI抑制剂为酪氨酸激酶抑制剂TKI。
与现有技术相比,本发明具有以下有益效果:
本发明提供了隐丹参酮和TKI抑制剂联用在制备Ph+急性淋巴细胞白血病化疗药物或化疗增敏药物中的应用,将隐丹参酮和抗癌药物进行定量配伍联用,可爆发式的提高隐丹参酮和抗癌药物(伊马替尼等TKI抑制剂)的作用效果,以高效低毒地治疗急性淋巴细胞白血病;且上述配伍方式的药物使用量远远低于当前临床的药物使用量,不属于能够对机体造成伤害的范围。另外,隐丹参酮是一种天然的二萜醌类化合物,主要来源于中国传统草药丹参,易于制备且对人体毒性较低,应用性强。
因此,本发明用隐丹参酮与TKI抑制剂联用制备的化疗药物或化疗增敏药物不仅高效低毒,而且专一性强、见效快;且隐丹参酮和抗癌药物(TKI抑制剂)联用在制备急性淋巴细胞白血病治疗药物、耐药逆转药物或预后防复发的药物中具有重要的意义和广泛的应用前景,为靶向治疗急性淋巴细胞白血病提供了思路,并为临床上高效治疗急性淋巴细胞白血病提供了新技术、新方法和新手段。
附图说明
图1是20nmol/L、100nmol/L、500nmol/L和1μmol/L隐丹参酮联用不同浓度伊马替尼的药物配伍方式,对Ph+急性淋巴细胞白血病细胞株Sup-B15细胞的增殖抑制情况。
具体实施方式
以下结合具体实施例来进一步说明本发明,但实施例并不对本发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明,以下实施例所用试剂和材料均为市购。
实施例1隐丹参酮与伊马替尼联合用药在Ph+急性淋巴细胞白血病细胞株中的研究
选用一定浓度梯度的隐丹参酮与伊马替尼分别处理Ph+急性淋巴细胞白血病细胞株Sup-B15细胞24h,同时固定隐丹参酮的浓度、联合使用不同梯度浓度的伊马替尼处理Sup-B15细胞24h,用MTT比色法计算细胞在五种不同的药物处理模式下各自的增殖抑制强度。
具体研究方法如下:
1、实验细胞株
Sup-B15Ph+急性淋巴细胞白血病细胞株购自美国ATCC细胞库。
2、细胞培养:
Sup-B15细胞用完全培养基(含10%FBS和1%双抗的RPMI-1640培养基)进行常规细胞培养,培养时采用37℃恒温、5%CO2的条件进行。
3、药物母液配制实验:
取购自Selleck Chemicals公司的隐丹参酮粉末和购自Sigma公司的伊马替尼粉末,称重,并用DMSO溶液溶解,分别至终浓度为5mmol/L(CPT)和30mmol/L(IM)。
4、细胞增殖抑制实验:
(1)获取细胞
取培养至对数生长期的Sup-B15细胞,1000rpm离心3min进行收集,用含10%胎牛血清的RPIM 1640培养基重悬细胞,并将细胞悬液的浓度调至3×105个/mL,以98μL/孔的量将上述细胞悬液接入96孔板内,置于37℃,5%CO2培养箱中培养24h;
(2)加药处理
A.取配好的5mmol/L隐丹参酮母液用DMSO溶液稀释至工作浓度(20nmol/L、100nmol/L、500nmol/L和1μmol/L)的100倍,故配制浓度分别为2μmol/L、10μmol/L、0.05mmol/L和0.1mmol/L,吹打混匀;
B.取配好的30mmol/L伊马替尼母液用DMSO溶液稀释至工作浓度(10nmol/L、50nmol/L、100nmol/L、500nmol/L和1μmol/L)的100倍,故配制浓度分别为1μmol/L、5μmol/L、10μmol/L、0.05mmol/L和0.1mmol/L,吹打混匀;
C.在步骤(1)中96孔板内的每孔细胞悬液中加入稀释好的药物,分为伊马替尼单独用药组、20nmol/L隐丹参酮与伊马替尼联合用药组、100nmol/L隐丹参酮与伊马替尼联合用药组、500nmol/L隐丹参酮与伊马替尼联合用药组和1μmol/L隐丹参酮与伊马替尼联合用药组:
伊马替尼单独用药组:每孔加入1μL步骤B中稀释好的各浓度伊马替尼溶液和1μLDMSO溶液,伊马替尼0nmol/L对照孔为仅加入2μL DMSO溶液,晃动培养板以混匀,置于37℃,5%CO2培养箱中培养24h;
20nmol/L隐丹参酮与伊马替尼联合用药组:每孔加入1μL步骤A中稀释好的2μmol/L隐丹参酮溶液和1μL步骤B中稀释好的各浓度伊马替尼溶液,隐丹参酮20nmol/L伊马替尼0nmol/L对照孔为加入1μL步骤A中稀释好的2μmol/L隐丹参酮溶液和1μL DMSO溶液,晃动培养板以混匀,置于37℃,5%CO2培养箱中培养24h;
100nmol/L隐丹参酮与伊马替尼联合用药组:每孔加入1μL步骤A中稀释好的10μmol/L隐丹参酮溶液和1μL步骤B中稀释好的各浓度伊马替尼溶液,隐丹参酮100nmol/L伊马替尼0nmol/L对照孔为加入1μL步骤A中稀释好的10μmol/L隐丹参酮溶液和1μL DMSO溶液,晃动培养板以混匀,置于37℃,5%CO2培养箱中培养24h;
500nmol/L隐丹参酮与伊马替尼联合用药组:每孔加入1μL步骤A中稀释好的0.05mmol/L隐丹参酮溶液和1μL步骤B中稀释好的各浓度伊马替尼溶液,隐丹参酮500nmol/L伊马替尼0n mol/L对照孔为加入1μL步骤A中稀释好的0.05mmol/L隐丹参酮溶液和1μLDMSO溶液,晃动培养板以混匀,置于37℃,5%CO2培养箱中培养24h;
1μmol/L隐丹参酮与伊马替尼联合用药组:每孔加入1μL步骤A中稀释好的0.1mmol/L隐丹参酮溶液和1μL步骤B中稀释好的各浓度伊马替尼溶液,隐丹参酮1μmol/L伊马替尼0nmol/L对照孔为加入1μL步骤A中稀释好的0.1mmol/L隐丹参酮溶液和1μL DMSO溶液,晃动培养板以混匀,置于37℃,5%CO2培养箱中培养24h;
(3)在各孔细胞悬液内加入15μLMTT溶液(MTT试剂盒购自Promega公司,USA),置于37℃,5%CO2培养箱中培养4h;
(4)在步骤(3)中各孔内加入100μL STOP溶液,置于37℃,5%CO2培养箱中培养24h;
(5)取出96孔培养板,分别于570nm波长和630nm波长的激发光下检测各孔的吸光值,A570-A630,即为各孔真实的吸光值,反应的是各孔中细胞的存活率,据此可算出各孔细胞在药物作用下的增殖抑制情况。
5、实验结果
结果如附图1所示,隐丹参酮与伊马替尼的联合使用能够起到爆发式的协同增效作用,当20nmol/L隐丹参酮配伍10nmol/L伊马替尼时,细胞的存活率仅为24%,即可抑制76%的细胞增殖,此配伍方式的使用量均远远低于目前临床的使用量、不属于能够对机体造成伤害的范围。
以上具体实施方式为便于理解本发明而说明的较佳实施例,但本发明并不局限于上述实施例,即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明所选用原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围之内。
Claims (7)
1.隐丹参酮和抗癌药物联用在制备急性淋巴细胞白血病的治疗和/或预防药物中的应用。
2.隐丹参酮和抗癌药物联用在制备急性淋巴细胞白血病耐药逆转药物和/或预后防复发的药物中的应用。
3.根据权利要求1或2所述的应用,其特征在于,所述抗癌药物为TKI抑制剂。
4.根据权利要求3所述的应用,其特征在于,所述TKI抑制剂为伊马替尼、达沙替尼、尼洛替尼或普纳替尼中的一种或几种的组合。
5.根据权利要求1或2所述的应用,其特征在于,所述急性淋巴细胞白血病为Ph+急性淋巴细胞白血病。
6.根据权利要求1或2所述的应用,其特征在于,隐丹参酮和抗癌药物联用的比例为0.001~100:1。
7.一种急性淋巴细胞白血病的治疗药物,其特征在于,包含有效量的隐丹参酮和抗癌药物;所述抗癌药物为TKI抑制剂。
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