CN118286244A - 澳洲茄碱在制备治疗口腔鳞癌药物中的应用 - Google Patents
澳洲茄碱在制备治疗口腔鳞癌药物中的应用 Download PDFInfo
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- CN118286244A CN118286244A CN202410446637.7A CN202410446637A CN118286244A CN 118286244 A CN118286244 A CN 118286244A CN 202410446637 A CN202410446637 A CN 202410446637A CN 118286244 A CN118286244 A CN 118286244A
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- solasonine
- oral squamous
- medicament
- cell carcinoma
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Abstract
本发明提供一种澳洲茄碱在制备治疗口腔鳞癌药物中的应用。研究发现澳洲茄碱对口腔鳞癌细胞具有较好的抑制效果,可用于临床治疗口腔鳞癌。
Description
技术领域
本发明涉及医疗药物领域,特别是涉及澳洲茄碱在制备治疗口腔鳞癌药物中的应用。
背景技术
除心血管疾病外,癌症是引起人类死亡的主要疾病。OSCC(OralSquamous CellCarcinoma,口腔鳞状细胞癌),是口腔黏膜上皮的鳞状细胞癌之一。尽管OSCC一般位于浅表位置,但由于早期阶段没有指示性症状表现,多数患者在发现时已经处于晚期(III或IV期),与I期和II期患者相比,IV期OSCC患者的肿瘤淋巴结转移率较高,导致患者预后不良。目前为止,OSCC的治疗方法通常是手术切除辅助化学药物治疗和放射治疗,必要时进行颈淋巴结清扫术。I期或II期OSCC患者通过适当的治疗,五年生存率约为85%。而发生肿瘤转移的II期和IV期OSCC患者采取手术和放化疗治疗后,仅有45%左右可存活两年以上。虽然近年来OSCC的治疗效果取得了显著的进展,然而,肿瘤对化疗药物的耐药性及其毒副作用(如肝毒性和心脏毒性)限制了其疗效。
近年来,越来越多的天然产物因其多靶向性、易得性、低成本和低毒性等优点成为有效的抗癌药物。
发明内容
鉴于以上所述现有技术的缺点,本发明的目的在于提供澳洲茄碱在制备治疗口腔鳞癌药物中的应用,用于解决现有技术中口腔鳞癌缺乏有效的治疗药物的问题。
本发明的一方面提供了澳洲茄碱或其水合物、药学上可接受的盐、互变异构体、立体异构体、前体化合物中的至少一种作为活性成分在制备治疗口腔鳞癌药物中的应用。所述澳洲茄碱的分子结构式如式I。分子式:C45H73NO16;分子量:884.06,Cas:19121-58-5。
进一步地,药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,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、苯甲磺酸,苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸。
本发明的另一方面提供了一种用于治疗口腔鳞癌的药物,所述药物含有治疗有效量的澳洲茄碱或其水合物、药学上可接受的盐、互变异构体、立体异构体、或前体化合物。
进一步地,所述药物还包括人体可接受的载体。这类载体包括(但并不限于):盐水、缓冲液、葡萄糖、水、甘油、乙醇、粉剂、及其组合。
进一步地,所述药物具有以下功能:
a)抑制口腔鳞癌细胞的生长;
b)抑制口腔鳞癌细胞的克隆;
c)抑制口腔鳞癌细胞的增殖。
本发明另一方面还提供了一种药物组合物,所述药物组合物的主要有效成分之一为澳洲茄碱或其水合物、药学上可接受的盐、互变异构体、立体异构体、或前体化合物。
上述各种剂型的药物均可以按照药学领域的常规方法制备。具体地说,根据本发明的药物剂型包括但不限于:片剂、胶囊剂、颗粒剂、粉剂、注射液、注射用粉剂、透皮贴剂、软膏剂、凝胶剂、栓剂、口服溶液、口服混悬液、注射用乳剂、口服乳剂等、缓释片剂、控释片剂。
用于口服施用的剂型可包括例如片剂、丸剂、硬或软胶囊剂、溶液剂、混悬剂、乳剂、糖浆剂、散剂、粉剂、细粒剂、颗粒剂、小丸剂、酏剂等,并不限于此。除了活性成分外,这些制剂还可包含稀释剂(例如乳糖、右旋糖、蔗糖、甘露糖醇、山梨糖醇、纤维素和甘氨酸)、润滑剂(例如二氧化硅、滑石、硬脂酸或其镁盐、钙盐和聚乙二醇)。片剂还可包含粘合剂,例如硅酸镁铝、淀粉糊、明胶、黄芪胶、甲基纤维素、羧甲基纤维素钠和聚乙烯吡咯烷。必要时,其还可包含药用添加剂,例如崩解剂(如淀粉、琼脂、海藻酸或其钠盐)、吸收剂、着色剂、香味剂、甜味剂等。片剂可根据常用的混合、造粒或包衣的方法制备。
用于肠道外施用的剂型可包括例如注射剂、药用滴剂、软膏剂、洗剂、凝胶剂、乳膏、喷雾剂、混悬剂、乳剂、栓剂、贴剂等,并不限于此。
根据本公开的药物组合物可口服或非肠道例如经直肠、经局部、经皮肤、经静脉内、经肌内、经腹膜内或经皮下施用。
本发明的药物、制剂或者药物组合物可通过常规的方式施用于所需的对象(如人和非人哺乳动物)。代表性的施用方式包括(但并不限于):口服或注射(包括静脉注射、静脉滴注、肌肉注射或皮下注射等中的一种或多种)等中的一种或多种给药途径。使用药物组合物时,是将安全有效量的药物施用于哺乳动物。当然,具体剂量和方法还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
如上所述,本发明的澳洲茄碱在制备治疗口腔鳞癌药物中的应用,具有以下有益效果:
澳洲茄碱能够有效的抑制口腔鳞癌细胞的生长、增殖。对于口腔鳞癌的治疗具有十分重要的积极作用。
附图说明
图1显示CCK8检测CAL-27、WSU-HN30与HACAT细胞孵育不同浓度的澳洲茄碱(20,24,28和32μM)的细胞存活率。
图2显为克隆形成检测CAL-27、WSU-HN30与HACAT细胞孵育不同浓度的澳洲茄碱(24,28和32μM)的细胞增殖。
图3显示Edu荧光检测CAL-27、WSU-HN30与HACAT细胞孵育不同浓度的澳洲茄碱(24,28和32μM)的细胞增殖(红色:EdU,蓝色:Hoechst33342)。
图4显示实施例4实验结果图,其中A.裸鼠移植瘤大体图。B.裸鼠移植瘤不同时间点的体积图。C.裸鼠不同时间点的体重。
具体实施方式
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体,例如:烯醇与相应的酮。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,例如:顺反异构体、对映异构体、构象异构体等。
术语“前体化合物”是指在体外无活性,但能够在生物体内进行代谢或化学反应转化为本发明的活性成分,从而发挥其药理作用的化合物。
术语“药物组合物”具有其一般含义。此外,本发明的“药物组合物”还可以以保健品、功能性食品、食品、食品添加剂等形式存在或提供。可采用制药领域特别是制剂领域中的常规技术,通过药品生产中常用的提取分离纯化手段得到本发明的药物组合物的原料的有效成分,任选地与一种或更多种药学可接受的载体或赋形剂混合,然后形成所需的剂型,来制备本发明的药物组合物。根据本发明的药物组合物,其为可以适用于口服给药、胃肠外给药或局部给药、外用给药的药物制剂。本发明的药物组合物可以制成片剂、粉剂、颗粒剂、胶囊、口服液等多种形式。
以上为澳洲茄碱的结构式,该生物碱从中药龙葵的生物碱中提取,属于甾体生物碱的胆甾烷衍生物。
以下通过特定的具体实例说明本发明的实施方式,本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用,本说明书中的各项细节也可以基于不同观点与应用,在没有背离本发明的精神下进行各种修饰或改变。须知,下列实施例中未具体注明的工艺设备或装置均采用本领域内的常规设备或装置。此外应理解,本发明中提到的一个或多个方法步骤并不排斥在所述步骤前后还可以存在其他方法步骤或在这些明确提到的步骤之间插入其他方法步骤,除非另有说明;还应理解,本发明中提到的一个或多个设备/装置之间的组合、连接关系并不排斥在所述组合设备/装置前后还可以存在其他设备/装置或在这些明确提到的两个设备/装置之间插入其他设备/装置,除非另有说明。而且,除非另有说明,各方法步骤的编号仅为鉴别各方法步骤的便利工具,而非为限制各方法步骤的排列次序或限定本发明可实施的范围,其相对关系的改变或调整,在无实质变更技术内容的情况下,当亦视为本发明可实施的范畴。
实施例1不同浓度的澳洲茄碱干预口腔鳞癌细胞系CAL-27与WSU-HN30细胞生长抑制
1.1实验材料
人口腔鳞癌细胞系CAL-27与WSU-HN30与人正常角质形成细胞HACAT购自ATCC。RPMI1640,胎牛血清,青霉素和链霉素购自美国Invitrogen公司。CCK-8试剂购自上海陶术生物。
1.2实验方法
CAL-27、WSU-HN30与HACAT细胞用含10%胎牛血清,100U/ml青霉素和100μg/ml链霉素的RPMI1640培养基,于37℃,5%CO2及饱和湿度的培养箱中培养,用0.25%膜蛋白酶消化传代,取对数生长期细胞用于实验。
将细胞制成细胞悬液(5×104个/ml),以5×103个/孔CAL-27、WSU-HN30与HACAT接种到96孔板中。待细胞贴壁生长状态良好时,弃原培养液,更换含2.5%血清的培养液,加入澳洲茄碱与细胞共孵48小时后,加入10μ1CCK8置培养箱反应4小时。弃培养液,加100μ1DMSO充分溶解,最后在吸光度450nm处测定吸光值,所得的值再减去空白的吸光值。细胞抑制率计算公式:
As:实验孔(含细胞的培养基、CCK-8溶液和药物溶液)
Ac:对照孔(含细胞的培养基和CCK-8溶液而没有药物溶液)
Ab:空白孔(不含细胞和药物溶液,CCK-8溶液)
抑制率=[(Ac-As)/(Ac-Ab)]×100%
1.3实验结果
结果如图1所示,澳洲茄碱具有抑制人口腔鳞癌细胞系CAL-27与WSU-HN30细胞生长的活性。澳洲茄碱于加20,24,28和32μM抑制CAL-27与WSU-HN30细胞生长,说明澳洲茄碱能够浓度依赖性地抑制人口腔鳞癌细胞生长。对于人正常角质形成细胞而言,当澳洲茄碱浓度为32μM显著抑制其细胞生长,且抑制率为18.3%。
实施例2澳洲茄碱抑制人口腔鳞癌细胞系CAL-27与WSU-HN30细胞克隆形成
2.1实验材料
人口腔鳞癌细胞系CAL-27与WSU-HN30与人正常角质形成细胞HACAT购自ATCC。RPMI1640,胎牛血清,青霉素和链霉素购自美国Invitrogen公司。结晶紫试剂购自美国Sigma公司。
2.2实验方法
人口腔鳞癌细胞系CAL-27与WSU-HN30与人正常角质形成细胞HACAT用含10%胎牛血清,100U/ml青霉素和100μg/ml链霉素的RPMI1640培养基,于37℃,5%CO2及饱和湿度的培养箱中培养,用0.25%膜蛋白酶消化传代,取对数生长期细胞用于实验。
将处于对数生长期的细胞胰酶消化后,于6孔板培养板中各实验组接种1,000个细胞/孔。继续培养到14天或绝大多数单个克隆中细胞数大于50为止,中途每隔3天进行换液并观察细胞状态。克隆完成后,在显微镜下对细胞进行拍照,然后PBS洗涤1次,每孔加入1mL4%多聚甲醛固定30-60min,PBS洗涤1次。每孔加入结晶紫染液1ml,染细胞10-20min。PBS洗涤细胞数次,并于显微镜下计数。
2.3实验结果
结果如图3所示,澳洲茄碱具有抑制人口腔鳞癌细胞系CAL-27与WSU-HN30细胞增殖。澳洲茄碱于加24、48和32μM抑制CAL-27与WSU-HN30细胞增殖,说明澳洲茄碱能够浓度依赖性地抑制人口腔鳞癌细胞增殖。对于人正常角质形成细胞而言,当澳洲茄碱浓度为32μM显著抑制其细胞增殖。
实施例3澳洲茄碱抑制人口腔鳞癌细胞系CAL-27与WSU-HN30细胞增殖
3.1实验材料
人口腔鳞癌细胞系CAL-27与WSU-HN30与人正常角质形成细胞HACAT购自ATCC。RPMI1640,胎牛血清,青霉素和链霉素购自美国Invitrogen公司。EdU细胞增殖检测试剂盒购自碧云天公司。
3.2实验方法
人口腔鳞癌细胞系CAL-27与WSU-HN30与人正常角质形成细胞HACAT用含10%胎牛血清,100U/ml青霉素和100μg/ml链霉素的RPMI1640培养基,于37℃,5%CO2及饱和湿度的培养箱中培养,用0.25%膜蛋白酶消化传代,取对数生长期细胞用于实验。将细胞制成细胞悬液(5×104个/ml),以5×103个/孔CAL-27与WSU-HN30接种到96孔板中。待细胞贴壁生长状态良好时,弃原培养液,更换含2.5%血清的培养液,加入澳洲茄碱与细胞共孵48小时。用完全培基稀释EdU至20μM,96孔板中每孔加入100μl稀释好的EdU工作液,使其终浓度为10μM,37℃继续孵育2小时。去除细胞培养基,并固定、通透。每孔加入50μl反应液孵育。去除反应液后使用每孔加入100μl 1×的Hoechst33342避光染色10分钟。使用共聚焦显微镜拍照并计数。
3.3实验结果
结果如图3所示,澳洲茄碱具有抑制人口腔鳞癌细胞系CAL-27与WSU-HN30细胞增殖的作用。澳洲茄碱于加24、48和32μM抑制CAL-27与WSU-HN30细胞中EDU的荧光强度,说明澳洲茄碱能够浓度依赖性地抑制人口腔鳞癌细胞增殖。
实施例4澳洲茄碱抑制裸鼠移植瘤增殖
4.1实验材料
人口腔鳞癌细胞系CAL-27与WSU-HN30与人正常角质形成细胞HACAT购自ATCC。RPMI1640,胎牛血清,青霉素和链霉素购自美国Invitrogen公司。EdU细胞增殖检测试剂盒购自碧云天公司。6周龄雄性BALB/c Nude裸鼠,购自斯莱克实验动物有限公司。
4.2实验方法
动物造模与药物干预:使用6周龄雄性BALB/c Nude裸鼠,将小鼠分为空白对照组(Control)澳洲茄碱干预组低剂量组(5mg/kg)以及澳洲茄碱干预组高剂量组(10mg/kg),每组6只小鼠。在每只鼠右侧腋下注射8×105个人口腔鳞癌细胞系CAL-27与WSU-HN30细胞。一周后开始给药,空白对照组每周瘤周注射生理盐水0.05mL,澳洲茄碱干预组每周两次腹腔注射澳洲茄边碱5或10mg/kg,并在4周后取出肿瘤并测量体积拍照。
4.3实验结果
如图4所示,通过每周两次腹腔注射5或10mg/kg小鼠体重的澳洲茄碱后,在4周后能显著抑制小口腔鳞癌移植瘤的体积,且均有显著差异。此外,每周两次腹腔注射澳洲茄碱并不会对裸鼠的体重产生影响。
以上的实施例是为了说明本发明公开的实施方案,并不能理解为对本发明的限制。此外,本文所列出的各种修改以及发明中方法、组合物的变化,在不脱离本发明的范围和精神的前提下对本领域内的技术人员来说是显而易见的。虽然已结合本发明的多种具体优选实施例对本发明进行了具体的描述,但应当理解,本发明不应仅限于这些具体实施例。事实上,各种如上所述的对本领域内的技术人员来说显而易见的修改来获取发明都应包括在本发明的范围内。
Claims (8)
1.澳洲茄碱或其水合物、药学上可接受的盐、互变异构体、立体异构体、前体化合物中的至少一种作为活性成分在制备治疗口腔鳞癌药物中的应用。
2.根据权利要求1所述的应用,其特征在于:药学上可接受的盐包括无机盐和有机盐。
3.根据权利要求1所述的应用,其特征在于:所述盐是澳洲茄碱与酸形成的盐,所述酸选自以下任意一种:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,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、苯甲磺酸,苯磺酸、天冬氨酸、谷氨酸。
4.一种用于治疗口腔鳞癌的药物,其特征在于:所述药物含有治疗有效量的澳洲茄碱或其水合物、药学上可接受的盐、互变异构体、立体异构体、或前体化合物。
5.根据权利要求4所述的药物,其特征在于:所述药物还包括人体可接受的载体。
6.根据权利要求5所述的药物,其特征在于:所述载体选自:盐水、缓冲液、葡萄糖、水、甘油、乙醇、粉剂、或其组合。
7.根据权利要求4所述的药物,其特征在于:所述药物具有以下功能:
a)抑制口腔鳞癌细胞的生长;
b)抑制口腔鳞癌细胞的克隆;
c)抑制口腔鳞癌细胞的增殖。
8.一种药物组合物,其特征在于:所述药物组合物的主要有效成分之一为澳洲茄碱或其水合物、药学上可接受的盐、互变异构体、立体异构体、或前体化合物。
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