CN105311004B - 姜黄素及其药用盐的应用 - Google Patents
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Abstract
本发明涉及姜黄素及其药用盐在制备抗肿瘤相关性综合症药物中的应用。与目前常规的抗肿瘤化疗药物不但无法避免或减轻肿瘤相关性综合症、而且能够显著提高贫血等肿瘤相关性综合症的发生率和发病程度的作用特点不同，姜黄素具有在抑制肿瘤生长的同时、显著地抑制肿瘤相关性综合症的作用，为抗肿瘤相关性综合症药物的开发提供了新的思路。
Description
技术领域
本发明涉及一种抗肿瘤剂，特别是，涉及姜黄素及其药用盐在制备抗肿瘤相关性综合症药物中的应用。
背景技术
肿瘤相关性综合症严重影响病人的生存质量，是导致肿瘤患者死亡的一个重要原因。肿瘤相关性综合症包括：造血功能障碍、内分泌失调、腹水、肝脏损伤、脾脏损伤、肾功能损伤、胃肠道功能紊乱、肌肉萎缩等。以贫血为例，贫血是恶性肿瘤患者常见的并发症，据报道超过50％的肿瘤病人患有贫血。贫血的严重程度与许多因素有关，包括疾病进展和使用的化疗药物的种类，以及年龄的增加和潜在感染的发生等。各种肿瘤贫血发生率为：妇科肿瘤为81％，肺癌为77％，淋巴瘤与骨髓瘤为73％，胃肠道肿瘤为61％，乳腺癌为62％，泌尿生殖系肿瘤为51％。化疗疗程与贫血发生率和贫血程度有明显关系，Coiffier等对超过1000名肿瘤患者的调查显示化疗1个月后贫血发生率开始增长，接受化疗10～12个月的病人发生中度(血红蛋白8～10.0g/dl)或重度(血红蛋白＜8.0g/dl)贫血者在50％以上。有效控制和治疗贫血等肿瘤相关性综合症在肿瘤的综合治疗中具有重要意义。
发明内容
本发明要解决的技术问题是：提供一种姜黄素的新用途，具体涉及姜黄素及其药用盐在制备抗肿瘤相关性综合症药物中的应用。
为解决上述技术问题，本发明采用的技术方案如下：
姜黄素及其药用盐在制备抗肿瘤相关性综合症药物中的应用。
优选地，所述肿瘤为纤维肉瘤或非小细胞肺癌。
优选地，所述抗肿瘤相关性综合症药物的制剂形式为液体制剂、颗粒剂、片剂、冲剂、胶丸、胶囊、缓释剂、口崩制剂或注射剂。
优选地，所述姜黄素药用盐为姜黄素与无机酸形成的盐。
优选地，所述无机酸为盐酸、氢溴酸、硫酸、硝酸和磷酸中任一种或几种。
优选地，所述姜黄素药用盐为姜黄素与有机酸形成的盐。
优选地，所述有机酸为甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸和甲基苯磺酸中任一种或几种。
优选地，所述姜黄素药用盐为姜黄素与酸性氨基酸的酸形成的盐。
优选地，所述酸性氨基酸为天门氨酸或谷氨酸。
以姜黄素为主要成分的植物在制备抗肿瘤相关性综合症药物或食品中的应用。
本发明的有益效果在于：
1、与目前常规的抗肿瘤化疗药物不但无法避免或减轻肿瘤相关性综合症、而且能够显著提高贫血等肿瘤相关性综合症的发生率和发病程度的作用特点不同，姜黄素具有在抑制肿瘤生长的同时、显著地抑制肿瘤相关性综合症的作用，为抗肿瘤相关性综合症药物的开发提供了新的思路；
2、姜黄素药用盐具有相同的功效条件下，使得姜黄素具有更多的保存状态，适用范围更大；
3、姜黄素及其药用盐在抗肿瘤相关性综合症药物中作为主要成分，保证了抗肿瘤的同时，显著地抑制肿瘤相关性综合症，具有更好的药用效果，便于大规模生产和推广应用；
4、姜黄素是从姜黄的根茎中提取的一种酚类色素，在食品生产中用于肠类制品、罐头、酱卤制品等产品的着色，由于姜黄素同时是一种食品原料，因此，以姜黄素为主要活性成分的植物能够用以制备具有抗肿瘤相关性综合症的食品或者药物。
附图说明
图1为姜黄素治疗肿瘤动物模型实验结果；
图2为姜黄素治疗对小鼠肿瘤重量及肝脾系数实验结果；
图3为姜黄素治疗对小鼠贫血症状分析实验结果。
具体实施方式
实施例1抗肿瘤动物模型实验
目前常规的抗肿瘤药物在产生抗肿瘤效果的同时，一般都具有毒副作用。本实验中我们评价了姜黄素的抗肿瘤效果，同时通过治疗后动物体重的变化考察了药物的毒性。鉴于化疗药物治疗及其疗程与肿瘤相关性综合症发生率及其严重程度有明显关系，本实验中阳性对照采用目前国际上最为先进的抗肿瘤抗体药物作为对照。T241-VEGF是一种肿瘤生长快速、并且肿瘤相关性综合症明显的肿瘤模型。
我们将雌性C57BL/6小鼠(SPF级，6-8周龄，上海斯莱克实验动物有限责任公司生产)适应饲养2-3天，皮下接种前一天用剃毛器剃除背颈部体毛以便进行肿瘤细胞皮下接种。将肿瘤细胞T241-VEGF收集，并用PBS洗涤2次后，用PBS重悬，计数后用PBS稀释为1*107个cells/ml，冰上放置准备接种。小鼠用7％水合氯醛进行麻醉，0.1ml/只，腹腔注射；待小鼠完全麻醉后，用1ml医用一次性注射器对小鼠进行背颈部皮下接种肿瘤细胞T241-VEGF，1*106/只。将接种后的小鼠随机分组(每组8只)，称重，分组及给药治疗。本试验中姜黄素(Sigma公司生产,cat no.C1386-10G)用DMSO配置为1mol/L，给药之前用20％Tween-80(PBS配置)分别稀释为2.5mM，5mM和10mM。具体情况及给药方案如下：对照组(Control)：20％Tween-80，0.1ml/只；姜黄素低剂量组(Curcumin-2.5mM)：2.5mM Curcumin,0.1ml/只，连续给药14天；姜黄素中剂量组(Curcumin-5mM)：5mM Curcumin,0.1ml/只，连续给药14天；姜黄素高剂量组(Curcumin-10mM)：10mM Curcumin,0.1ml/只，连续给药14天；阳性对照组(PC：人源化抗VEGF单克隆抗体药物，江苏先声药业有限公司生产)：2mg/ml,0.1ml/只，每周2次，共给药4次。动物隔天称重，肿瘤长起后，用游标卡尺隔天量瘤体积。
结果如图1-A所示。姜黄素高中低三剂量均能抑制T241-VEGF肿瘤的生长，其中5mM和10mM剂量与对照组相比，最终的肿瘤体积呈显著差异(p<0.01或p<0.001),2.5mM组小鼠的肿瘤体积亦有一定的抑制。与肿瘤体积结果相对应的肿瘤重量结果见图1-B，结果显示，5mM和10mM剂量组的肿瘤重量与对照组呈显著差异，表明5mM和10mM两个剂量的姜黄素能够显著抑制T241-VEGF肿瘤的生长。无论是姜黄素高中低剂量组的体重都没有降低，而且显著好于阳性对照药物，显示其毒性甚至显著好于目前国际上最为先进的抗肿瘤抗体药物。姜黄素高中低三个剂量组动物的体重都与同期饲养的正常动物体重变化一致，而阳性对照药物组动物的体重在治疗则显著低于正常动物及姜黄素高中低三个剂量组动物。
实施例2各组小鼠肿瘤重量及肝脾系数实验
为了进一步确证姜黄素各剂量组的抗肿瘤效果、及其对肝脾的影响。我们在给药结束后隔天，处理各组动物，解剖得到肿瘤，肝脏，脾脏和肾脏，称重，将各组织进行固定保存。结果如图2，姜黄素对由于T241-VEGF肿瘤引发的肝脏肿大和脾脏肿大的改善结果明显。结果显示，肿瘤对照组小鼠的肝脏系数和脾脏系数与正常小鼠相比呈显著差异(p<0.01),5mM和10mM姜黄素能显著改善肝脏肿大(p<0.05)，同时10mM姜黄素能显著改善脾脏肿大(p<0.05)。
实施例3各组小鼠贫血症状分析实验
给药结束后隔天，处理各组动物，称重后摘眼球取血(存放入已加入20ul 0.5MEDTA的1.5ml EP管)，进行血相分析，评价姜黄素对肿瘤相关性综合症贫血指标--小鼠红细胞数(RBC)，血红蛋白(HGB)，红细胞比容(HCT)和血小板数(PLT)的改善结果。
对于由T241-VEGF肿瘤动物模型诱发的肿瘤相关性综合症--小鼠贫血症状，我们对各组小鼠血液进行血相分析，结果见图3显示：与正常小鼠相比，对照组小鼠红细胞数(RBC)，血红蛋白(HGB)，红细胞比容(HCT)和血小板数(PLT)显著降低，表明T241-VEGF肿瘤模型能够产生肿瘤相关性综合症、即荷瘤鼠贫血症状。阳性单克隆抗体药物能够显著改善荷瘤鼠的贫血症状，但是阳性单克隆抗体药物能够产生小鼠红细胞数(RBC)、血红蛋白(HGB)、红细胞比容(HCT)过度升高的现象；姜黄素高中低三个剂量小鼠贫血症状改善非常明显，与对照组相比均呈显著差异，其中红细胞数，血红蛋白和红细胞比容与正常小鼠无统计学差异，10mM剂量的血小板与正常小鼠无统计学差异，表明姜黄素能够显著改善由肿瘤引发的贫血症状。
本发明同时以非小细胞肺癌A549为肿瘤模型进行了与上述实验完全相同的实验研究，获得了几乎完全相同的研究结果。
这个结果充分说明：按照目前已知的姜黄素抗肿瘤的6个作用机制，即诱导细胞凋亡，诱导细胞周期阻滞，阻断肿瘤细胞的生长信号传导，抑制肿瘤血管生成，抑制黏附分子的表达，增加化疗药物对癌细胞的敏感性(国际肿瘤学杂志2013,v40(11):823-826)，姜黄素应当与化疗药物类似(诱导细胞凋亡，诱导细胞周期阻滞，阻断肿瘤细胞的生长信号传导，增加化疗药物对癌细胞的敏感性，这是许多小分子化疗药物共有的作用特征)、具有提高肿瘤相关性综合症发生率及其严重程度的作用。但是本发明出乎意料地发现，姜黄素能够在显著抑制肿瘤生长的同时，能非常显著地抑制肿瘤相关性综合症，同时荷瘤动物的体重像正常动物一样增长，未发生任何毒副作用现象。
将姜黄素与盐酸、氢溴酸、硫酸、硝酸、磷酸等无机酸形成的药用盐，和与甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、对甲基苯磺酸等有机酸和天门氨酸、谷氨酸等酸性氨基酸的酸形成的药用盐进行实施例1-3的实验发现，姜黄素药用盐与姜黄素具有相同的效果。在进一步应用中，可以根据实际需要，将含有姜黄素及其药用盐的抗肿瘤相关性综合症药物的制剂形式为液体制剂、颗粒剂、片剂、冲剂、胶丸、胶囊、缓释剂、口崩制剂或注射剂。
以富含姜黄素的姜、芥末、咖哩等原料制备而成的动物食品进行实施例1-3的实验发现，富含姜黄素的食品与姜黄素具有相类似的效果。在进一步应用中，可以根据实际需要，将富含姜黄素的抗肿瘤相关性综合症食品的形态为液体口服液、颗粒剂、片剂、冲剂、胶丸、胶囊、缓释剂、口崩制剂。
综上所述，姜黄素具有在抑制肿瘤生长的同时、能显著地抑制肿瘤相关性综合症的作用，为抗肿瘤相关性综合症药物的开发提供了新的思路。
Claims (2)
1.姜黄素及其药用盐在制备抗纤维肉瘤或非小细胞肺癌相关性综合症药物中的应用，其特征在于，所述纤维肉瘤或非小细胞肺癌相关综合症为荷瘤鼠肝脏肿大、脾脏肿大或贫血。
2.如权利要求1所述的应用，其特征在于，所述抗肿瘤相关性综合症药物的制剂形式为颗粒剂、片剂、冲剂、胶丸、胶囊、缓释剂、口崩制剂或注射剂。
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| EP16789007.8A EP3292865A1 (en) | 2015-05-06 | 2016-04-11 | Use of curcumin and pharmaceutically acceptable salt thereof |
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| WO2016177013A1 (zh) | 2016-11-10 |
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