CN117442737A - α2-肾上腺素受体激动剂与阿片受体激动剂的联合应用 - Google Patents
α2-肾上腺素受体激动剂与阿片受体激动剂的联合应用 Download PDFInfo
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- CN117442737A CN117442737A CN202311442245.5A CN202311442245A CN117442737A CN 117442737 A CN117442737 A CN 117442737A CN 202311442245 A CN202311442245 A CN 202311442245A CN 117442737 A CN117442737 A CN 117442737A
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Abstract
本发明公开了α2‑肾上腺素受体激动剂与阿片受体激动剂的联合应用,本发明还提供了α2‑肾上腺素受体激动剂与阿片受体激动剂在抑制食管癌细胞或组织增殖、侵袭、迁移、上皮‑间质转化、乳酸生成、ATP生成、葡萄糖水平、糖代谢水平中的应用,并提供了相应的药物组合物或药盒,本发明还提供了α2‑肾上腺素受体激动剂联合阿片受体激动剂在抑制HK2和LDHA蛋白的表达水平中的应用。
Description
技术领域
本发明属于生物技术领域,涉及α2-肾上腺素受体激动剂与阿片受体激动剂的联合应用,具体涉及食管癌。
背景技术
食管癌是一种复杂而常见的癌症,具有很强的侵袭性。食管鳞状细胞癌(食管鳞癌,ESCC)是一种起源于食管癌的恶性上皮肿瘤,是食管癌最常见的亚型之一,主要表现为进行性吞咽困难。据报告,从2010年到2023年,男性和女性的ESCC发病率和死亡率每年都在上升,构成了一个严重的公共卫生问题。EC的发病机制与饮食习惯、环境因素、地理位置和性别有关。据统计,EC的总5年生存率为15%-25%,是男性癌症相关死亡的第六大原因,中国男性的患病率高于女性。临床上,食管癌的治疗多采用药物、手术、放疗和化疗。然而,这些治疗方法产生的副作用和患者预后不良仍然是主要问题,迫切需要探索新的治疗方式来改善EC患者的治疗和预后。
发明内容
为了解决现有技术中存在的技术问题,本发明提供了如下的技术方案:
本发明提供了α2-肾上腺素受体激动剂联合阿片受体激动剂在制备预防或治疗食管癌的药物组合物中的应用。
进一步,所述α2-肾上腺素受体激动剂包括右美托咪定及其药学上可接受的盐。
进一步,所述阿片受体激动剂包括阿片μ受体激动剂、阿片κ受体激动剂、阿片μ、κ受体激动剂。
进一步,所述阿片μ受体激动剂包括吗啡、芬太尼、舒芬太尼、瑞芬太尼、美沙酮、哌替啶、羟考酮及其药学上可接受的盐。
进一步,所述阿片κ受体激动剂包括纳布啡、喷他佐辛、布托啡诺、地佐辛及其药学上可接受的盐。
进一步,所述阿片μ、κ受体激动剂包括氨酚羟考酮、氨酚待因、氨酚氢可酮、氨酚曲马多、洛芬待因及其药学上可接受的盐。
进一步,所述食管癌包括食管鳞癌。
在某个具体的实施方案中,所述α2-肾上腺素受体激动剂具体为盐酸右美托咪定(DEX-HCI)。在某个具体的实施方案中,所述阿片受体激动剂具体为枸橼酸舒芬太尼(SFC)。在某些具体的实施方案中,所述食管癌是常规认知中
在某个具体的实施方案中,所述盐酸右美托咪定(DEX-HCI)的使用浓度范围1-50nmol/L,具体的,使用浓度包括1nmol/L、5nmol/L、10nmol/L、15nmol/L、20nmol/L、25nmol/L、30nmol/L、35nmol/L、40nmol/L、45nmol/L、50nmol/L。在某个具体的实施方案中,所述枸橼酸舒芬太尼(SFC)的使用浓度范围为0.05-2μmol/L,具体的,使用浓度包括0.05μmol/L、0.1μmol/L、0.15μmol/L、0.2μmol/L、0.25μmol/L、0.3μmol/L、0.35μmol/L、0.4μmol/L、0.45μmol/L、0.5μmol/L、0.55μmol/L、0.6μmol/L、0.65μmol/L、0.7μmol/L、0.75μmol/L、0.8μmol/L、0.85μmol/L、0.9μmol/L、0.95μmol/L、1μmol/L、1.05μmol/L、1.1μmol/L、1.15μmol/L、1.2μmol/L、1.25μmol/L、1.3μmol/L、1.35μmol/L、1.4μmol/L、1.45μmol/L、1.5μmol/L、1.55μmol/L、1.6μmol/L、1.65μmol/L、1.7μmol/L、1.75μmol/L、1.8μmol/L、1.85μmol/L、1.9μmol/L、1.95μmol/L、2μmol/L。
在某些具体的实施方案中,所述盐酸右美托咪定(DEX-HCI)与枸橼酸舒芬太尼(SFC)摩尔浓度之比范围为1:2000到1:1,在某个特定的实施方案中,所述盐酸右美托咪定(DEX-HCI)与枸橼酸舒芬太尼(SFC)摩尔浓度之比为1:50。
如本文所用,短语“药学上可接受的盐”是指感兴趣化合物的那些盐,所述盐在哺乳动物中局部应用是安全和有效的并具有所需生物学活性。药学上可接受的盐包括指定化合物中存在的酸性或碱性基团的盐。药学上可接受的酸加成盐包括,但不限于,盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、醋酸盐、乳酸盐、水杨酸盐、柠檬酸盐、酒石酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐(gentisinate)、延胡索酸盐、葡糖酸盐、葡萄糖醛酸盐、蔗糖盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和巴莫酸盐(pamoate)(即l,l'-亚甲基-二-(2-羟基-3-萘甲酸盐))。本发明使用的某些化合物可与各种氨基酸形成药学上可接受的盐。适当的碱盐包括,但不限于:铝、钙、锂、镁、钾、钠、锌和二乙醇胺盐。药学上可接受的盐的综述可以参见列出的文献:BERGE等.,66J.PHARM.SCI.1-19(1977)。
在某些具体的实施方案中,所述“治疗”是指疾病或病症或其至少一种可分辨的症状的改善、预防、或逆转。在某些具体的实施方案中,所述“治疗”是指与所要治疗疾病或病症相关的至少一种可测量生理参数的改善、预防、或逆转,所述参数并不一定是哺乳动物中可识别的,或被哺乳动物识别。在另一个实施方案中,“治疗”是指抑制或减缓疾病或病症的进程,可以是身体上的,如稳定可辨别的症状,或是生理学上的,如稳定生理参数,或者两者兼而有之。在另一个实施方案中,“治疗”是指延迟疾病或病症的发作。
在某些具体的实施方案中,使用感兴趣的化合物作为预防措施,如本文中所用,“预防”是指降低获得某种疾病或病症的风险。在某个具体的实施方案中,给有食管癌的对象使用指定的化合物作为预防措施,尽管还未表现出食管癌的症状或症状轻微。
本发明提供了一种药物组合物,所述药物组合物包括联合使用预防或治疗有效量的前面所述的α2-肾上腺素受体激动剂与阿片受体激动剂。
进一步,所述药物组合物还包括药学上可接受的辅料。
进一步,所述辅料包括载体、辅剂、赋形剂、稀释剂或其它液体溶媒、分散助剂、悬浮助剂、表面活性剂、等渗剂、增稠剂、乳化剂、防腐剂、固体粘合剂、润滑剂。
如本文所用,“预防或治疗有效量”的“α2肾上腺素受体激动剂与阿片受体激动剂”是指α2肾上腺素受体激动剂与阿片受体激动剂的用量在组织体系、动物、或人中诱发研究人员、兽医、医师或临床医生所寻求的生物学或医学反应,包括减轻所治疗疾病或病症的症状。
本发明提供了α2-肾上腺素受体激动剂联合阿片受体激动剂在抑制食管癌细胞或组织增殖、侵袭或迁移增殖、侵袭、迁移、上皮-间质转化、乳酸生成、ATP生成、葡萄糖水平、糖代谢水平中的应用。
进一步,所述应用用于与已知载体、佐剂和/或添加剂一起使用,以口服、经皮、静脉、皮下、皮内、肌肉内、直肠、阴道或舌下用药的全身给药。
在某些具体的实施方案中,可以采用任何适当的施药途径来递送附加治疗方法或药物,包括但不限于,口服、口内、直肠、胃肠外、局部、经表皮、透皮、皮下、肌肉内、鼻内、舌下、口腔含化、硬膜内、眼内、呼吸道内、或鼻部吸入。
进一步,所述应用用于局部应用时乳剂、软膏、糊剂、胶剂、溶液、喷雾剂、脂质体或水状胶质敷料的形式。
可用于本发明实施方式中局部给药的示范性制剂形式包括,但不限于:喷雾、薄雾、气溶胶、溶液、洗液、凝胶、乳膏、软膏、糊剂、油膏、乳剂和悬浮液。选择可局部施用的组合物依赖于一些因素,包括:待治疗或预防症状的性质、待施用的具体化合物和存在的其它赋形剂的生理化学特征、它们在制剂中的稳定性、可用的制造设备,和费用限制。
在某些具体的实施方案中,用于本发明的合适的缓冲剂包括但不限于:醋酸盐缓冲液、柠檬酸盐缓冲液、磷酸盐缓冲液、乳酸缓冲液和硼酸盐缓冲液。
进一步,所述α2-肾上腺素受体激动剂包括右美托咪定及其药学上可接受的盐。
进一步,所述阿片受体激动剂包括阿片μ受体激动剂、阿片κ受体激动剂、阿片μ、κ受体激动剂。
进一步,所述阿片μ受体激动剂包括吗啡、芬太尼、舒芬太尼、瑞芬太尼、美沙酮、哌替啶、羟考酮及其药学上可接受的盐。
进一步,所述阿片κ受体激动剂包括纳布啡、喷他佐辛、布托啡诺、地佐辛及其药学上可接受的盐。
进一步,所述阿片μ、κ受体激动剂包括氨酚羟考酮、氨酚待因、氨酚氢可酮、氨酚曲马多、洛芬待因及其药学上可接受的盐。
进一步,所述应用中所述的两种激动剂,以相对独立的配方与已知载体、佐剂和/或添加剂同时或立即连续应用,以达到一种结合的效果。
本发明提供了α2-肾上腺素受体激动剂联合阿片受体激动剂在抑制HK2和LDHA蛋白的表达水平中的应用。
本发明提供了一种抑制HK2和LDHA蛋白的表达水平的组合物,所述组合物包括以下组分或由以下组分组合而成:
1)第一活性成分,所述第一活性成分包括α2-肾上腺素受体激动剂;
2)第二活性成分,所述第二活性成分包括阿片受体激动剂。
进一步,所述组合物用于制备抑制食管癌细胞的药物。
如本文所用,术语“第一活性成分”、“α2-肾上腺素受体激动剂”或“第一制剂”可互换使用,指α2-肾上腺素受体激动剂。本发明的活性成分可以为药学上可接受的α2-肾上腺素受体激动剂的各种晶型、无定形、脱水物、溶剂化物、水合物、对映体,本发明中α2-肾上腺素受体激动剂即指本发明的第一活性成分。
如本文所用,术语“第二活性成分”、“第二制剂”或“阿片受体激动剂”可互换使用,指阿片受体激动剂,具体包括阿片μ受体激动剂、阿片κ受体激动剂、阿片μ、κ受体激动剂。本发明的活性成分可以为药学上可接受的阿片受体激动剂的各种晶型、无定形、脱水物、溶剂化物、水合物、对映体,本发明中阿片受体激动剂即指本发明的第二活性成分。
进一步,所述α2-肾上腺素受体激动剂包括右美托咪定及其药学上可接受的盐。
进一步,所述阿片受体激动剂包括阿片μ受体激动剂、阿片κ受体激动剂、阿片μ、κ受体激动剂。
进一步,所述阿片μ受体激动剂包括吗啡、芬太尼、舒芬太尼、瑞芬太尼、美沙酮、哌替啶、羟考酮及其药学上可接受的盐。
进一步,所述阿片κ受体激动剂包括纳布啡、喷他佐辛、布托啡诺、地佐辛及其药学上可接受的盐。
进一步,所述阿片μ、κ受体激动剂包括氨酚羟考酮、氨酚待因、氨酚氢可酮、氨酚曲马多、洛芬待因及其药学上可接受的盐。
本发明提供了一种非治疗目的的抑制体外细胞HK2和LDHA蛋白的表达水平的方法,所述方法包括使用前面所述的α2-肾上腺素受体激动剂与阿片受体激动剂的步骤。
本发明提供了一种药盒,所述药盒包括:
(i)含有α2-肾上腺素受体激动剂的第一制剂;
(ii)含有阿片受体激动剂的第二制剂;
(iii)使用说明书;
所述第一制剂选自:右美托咪定及其药学上可接受的盐;
所述第二制剂选自:阿片μ受体激动剂、阿片κ受体激动剂、阿片μ、κ受体激动剂。
联合用药过程中,药物的相互作用根据药物共同使用时的效应分为相加作用、协同作用、拮抗作用,协同作用是指联合用药的药物共同使用时的效应要比单独使用大很多倍,加和作用是指联合用药的药物共同使用时的效应要与单独使用相当,拮抗作用是指联合用药的药物共同使用时的效应要比单独使用小。在联用本发明中,首次发现第一制剂和第二制剂合用具有协同作用。
进一步,所述阿片μ受体激动剂包括吗啡、芬太尼、舒芬太尼、瑞芬太尼、美沙酮、哌替啶、羟考酮及其药学上可接受的盐。
进一步,所述阿片κ受体激动剂包括纳布啡、喷他佐辛、布托啡诺、地佐辛及其药学上可接受的盐。
进一步,所述阿片μ、κ受体激动剂包括氨酚羟考酮、氨酚待因、氨酚氢可酮、氨酚曲马多、洛芬待因及其药学上可接受的盐。
进一步,所述使用说明书中注明将所述第一制剂和第二制剂进行联用,从而治疗食管癌,或抑制食管癌组织或细胞的增殖、侵袭、迁移、上皮-间质转化、乳酸生成、ATP生成、葡萄糖水平、糖代谢水平。
当在试剂盒中使用时,本文所用的术语“使用说明书”包括:可以用于表达试剂盒指定用途有效性的出版物、记录、图标、或任何其他的表达媒介。例如,使用说明书可以贴在或包含于试剂盒的容器中。
进一步,所述在治疗食管癌,或抑制食管癌组织或细胞的增殖、侵袭、迁移、上皮-间质转化、乳酸生成、ATP生成、葡萄糖水平、糖代谢水平时第一制剂、第二制剂同时给药、分别给药或顺序给药。
本发明提供了一种体外非治疗性抑制食管癌细胞或组织的方法,所述方法包括将前面所述的药物组合物或前面所述的药盒施用到体外食管癌细胞或组织上的步骤。
进一步,所述抑制具体包括抑制食管癌组织或细胞的增殖、侵袭、迁移、上皮-间质转化、乳酸生成、ATP生成、葡萄糖水平、糖代谢水平。
附图说明
图1是KYSE30、KYSE520、KYSE140、KYSE40细胞中p-STAT 3和p-JAK的表达水平结果图;
图2是KYSE30细胞CCK-8实验和细胞克隆实验图;
图3是克隆实验结果图;
图4是伤口愈合实验结果图;
图5是Transwell实验结果图;
图6是免疫荧光法检测结果图;
图7是RO8191激活剂抵消了DEX-HCI和SFC对KEYSE30细胞的抑制作用结果图;
图8是KYSE30细胞的ATP水平、乳酸生成和葡萄糖检测结果图;
图9是加入RO8191激活剂抵消了DEX-HCI和SFC对KYSE30细胞的ATP水平、乳酸生成和葡萄糖抑制结果图;
图10是MMP2、MMP9、N-cadherin、Ecadherin蛋白的表达结果图;
图11是STAT3和JAK蛋白的表达结果图;
图12是RO8191抵消了DEX-HCI和SFC对STAT3/JAK/HIF-α信号通路的抑制作用结果图。
具体实施方式
除非另行定义,本文使用的所有技术和科学词语具有与本发明所属领域的任一普通技术人员通常理解相同的含义。或者,本文所用的某些术语具有说明书中列出的意义。本文引用的所有专利,公布的专利申请和出版物通过引用纳入本文,就如同在本文中全文列出那样。必须注意,本文及随附权利要求书中使用的单数形式“一个”、“一种”和“该”包括复数形式,除非文中另有明确指出。
实施例
1、实验方法
1)细胞培养
使用购于中国科学院上海细胞库的人食管鳞状细胞系KYSE30、KYSE520、KYSE140、KYSE40和人正常食管上皮细胞HEEC。细胞在含10%胎牛血清(ExCell Bio,YSN0121)和1%青霉素-链霉素混合物(Solarbio,P1400)的RPMI-1640培养基(Gibco,C11875500BT)中,在37℃,5%CO2培养箱(洁美电子,CI-191C)中培养。每两天更换一次培养基,让其自然生长到指数阶段,以供后续实验使用。
2)CCK-8实验
收集指数生长期的KYSE30细胞,丢弃培养基。PBS洗涤细胞3次,胰蛋白酶(Solarbio,P6730)消化2-3分钟,加入1640完全培养液终止,重悬。计数后将细胞转移至96孔板上,每孔3000个细胞孵育过夜,并分为四组,分别为DEX-HCI组(仅用DEX-HCI处理)、SFC组(仅用SFC处理)、DEX-HCI和SFC联合给药组和对照组。DEX-HCI组细胞用不同浓度梯度的药物处理,最终浓度分别为25、50、100、200nmol/L。SFC组细胞分别加入不同浓度梯度的药物,最终浓度分别为1.25、2.5、5、10μmol/L。共给药组分别加入不同浓度梯度的SFC(1.25μmol/L)和DEX-HCI(25nmol/L)。对照组给予相同体积的DMSO溶液处理。96孔板在培养箱中孵育48h后,每孔加入10μL CCK8(Solarbio,CA1210)溶液,孵育3h,采用酶免疫分析仪(Flash,ReadMax 1200)测定450nm处吸光度。
3)细胞体外克隆实验
使用指数生长期的KYSE30细胞,并进行细胞消化和细胞计数,如前面CCK-8试验所述。将细胞密度重悬至150个细胞/mL,在六孔板中每孔加入1mL细胞悬液与1mL 1640完全培养基混合,在37℃、5% CO2的培养箱中孵育过夜。每2d补加新鲜培养基,连续培养14d。然后丢弃培养基,用PBS溶液冲洗细胞3次,再用0.1%结晶紫(Solarbio,C8470)染色15分钟。PBS冲洗细胞3次,自然风干后拍照。使用Image J对图像进行分析。
4)伤口愈合实验
将细胞悬液接种于每孔5×105细胞的六孔板中,在细胞培养箱中孵育过夜,用10μL的移液针尖在六孔板底部画三条平行垂直线。丢弃培养基后,用PBS洗涤细胞3次,在六孔板中加入含有不同浓度梯度DEX-HCI(25nmol/L)和SFC(1.25μmol/L)药物溶液的无血清1640培养基,在培养箱中培养。分别于0h和12h从培养箱中取出六孔板,用显微镜(Shunyu,ICX41)在显示的水平线和垂直线相交处拍照。采用Image J对各组细胞迁移率进行统计分析。
5)Transwell实验
收集指数期KYSE30细胞,计数方法如上所述。用无血清1640培养基将细胞浓度稀释至1×106cells/mL,在凝胶处理后的腔中加入50μL细胞悬液。每孔加入不同浓度梯度无血清1640培养基中的DEX-HCI(25nmol/L)和SFC(1.25μmol/L)50μL,在培养箱中培养12h。下腔每孔加入500μL甲醇溶液25min,丢弃甲醇溶液,用PBS洗去多余的甲醇。下室每孔加入0.1%结晶紫溶液25min,拍照保存。
6)葡萄糖、乳酸和ATP含量测定
KYSE30细胞单独和联合处理24h后,收集细胞,用无菌细胞刮刀转移到1.5mL离心管中。加入1mL蒸馏水,超声枪粉碎细胞,4℃水浴静置10min,12000rpm离心15min。根据葡萄糖和乳酸含量测定试剂盒的说明,用紫外分光光度计在505nm处测定样品中的葡萄糖含量,在530nm处测定样品中的乳酸含量,并记录实验数据,以便后续进行统计分析。
7)免疫荧光
将细胞样品用4%多聚甲醛处理20min,再用0.5% Triton X-100孵育20min,加入牛血清白蛋白封闭细胞1h。一抗4℃孵育过夜,TBST洗涤,加入荧光二抗避光1h。玻片用DAPI孵育,避光5分钟,用抗荧光猝灭剂密封,在共聚焦显微镜下拍照保存,用Image J进行统计分析。
8)qPCR实验
指数生长期的KYSE30细胞用DEX-HCI和SFC处理24h,用无菌细胞刮板收集,转移到1.5mL离心管中。加入Trizol(Solarbio,15596026)1ml,多次移液,匀质液在15~30℃静置5min。按试剂盒要求提取RNA,立即使用或-80℃冰箱保存。
采用紫外可见分光光度计Q5000测定RNA浓度。按照逆转录试剂盒(TIANGEN,KR118)反应体系对RNA进行逆转录,逆转录后的cDNA立即使用或-80℃冰箱保存。采用QPCR检测试剂盒(TIANGEN,FP313)反应体系,在实时荧光定量仪(Bio-RAD,CFX Connect)上扩增cDNA浓度,收集原始数据进行后续分析。
9)Western blot
根据每个样品的体积,加入相应体积的裂解液样品,置于冰上25min。在4℃下,12000rpm离心10min,分离上清,得到提取的蛋白质。蛋白定量采用比胆霉素酸(BCA)蛋白定量试剂盒(Solarbio,PC0020)。根据蛋白定量结果,依次加入样品,在80v电压下进行凝胶电泳。35min后,调整电压至120V,维持60min,直至电泳结束。将凝胶夹盒置于trans-blot涡轮转移系统中,以260mA的恒流进行1小时转移。PVDF膜在5%脱脂奶粉中密封2h,用1×TBST溶液洗涤,每次30min,共3次,用相应的一抗在4℃孵育过夜。PVDF膜用1×TBST溶液洗涤3次,每次洗涤30min,5%脱脂奶粉处理,二抗孵育1h。用Image J对图像进行处理和分析,进行后续数据处理。β-actin(HUABiO,EM21002)Anti-JAK2antibody(HUABiO,M1501-8)P-JAK2(HUABiO,ET1607-34)STAT3(HUABiO,ET1607-38)p-STAT3(HUABiO,ET1603-40)HIF-1α(HUABiO,R1510-5)MMP2(Bioss,bs-4605R)MMP9(Bioss,bs-4593R)N-Cadherin(ABclonal,A19083)E-Cadherin(bioss,bs-1519R)Hexokinase II(ABclonal,A0994)PFKFB3(ABclonal,A3934)LDHA(ABclonal,A1146)CLUSTERIN(HUABiO,ER2001-58),Goat anti-rabbit(Bioss,K008),Goat anti-rat(Bioss,K009)。
10)统计分析
采用SPSS软件进行数据分析。计量数据以均数±标准差(SD)表示。通过单因素或双向方差分析(ANOVA)验证组间差异,然后进行LSD事后分析。P<0.05表示差异有统计学意义。
2、实验结果
1)DEX-HCI和SFC对KYSE30细胞增殖的抑制作用
在4种食管鳞癌细胞系(KYSE30、KYSE520、KYSE140、KYSE40)中,与人正常食管上皮细胞HCC相比,KYSE30细胞中p-STAT 3和p-JAK的表达上调最为显著,因此我们选择KYSE30作为下一步研究的对象,结果如图1所示。体外CCK-8实验和细胞克隆实验结果显示,DEX-HCI(1、10、100、1000ng/mL)-和SFC(1.25、2.5、5、10μM)处理的KYSE30细胞在处理48h后,细胞活力明显低于对照组,且呈浓度依赖性。与单独给药相比,DEX-HCI和SFC联合给药对KYSE30细胞活力的抑制作用增强,如图2所示。使用graphprism 9.5.0计算DEX-HCI的IC50为83.96nmol/L,SFC的IC50为2.173μmol/L,在随后的实验中,DEX-HCI用量为25nmol/L,SFC用量为1.25μmol/L。
为评价DEX-HCI与SFC合用的效果,采用Soriano等人的判断方法,协同指数(CI)0.2≤CI<0.4被认为是一个强大的协同作用。DEX-HCI与SFC的CI为0.27,表明DEX-HCI与SFC具有较强的协同效应。CI=CDA/SDA+CDB/SDB(A为DEX-HCI;B为SFC,CD为两药联合达到生长抑制率X时的浓度;SD为单独用药达到X生长抑制率时的药物浓度)。
克隆实验结果显示,DEX-HCI和SFC能够抑制KYSE30细胞的增殖能力,并且与单给药相比,DEX-HCI和SFC联合给药对KYSE30细胞的抑制作用增强,表明DEX-HCI和SFC联合给药更有效,结果如图3所示。
2)DEX-HCI和SFC对KYSE30细胞侵袭和迁移能力的影响
采用伤口愈合实验和Transwell实验验证DEX-HCI和SFC对细胞迁移和侵袭的影响。伤口愈合实验结果显示,单独用DEX-HCI(25nmol/L)或单独用SFC(1.25μmol/L)处理KYSE30细胞12h后,KYSE30细胞的迁移和愈合能力均受到抑制,而联合给药对KYSE30细胞迁移的抑制作用增强。两种药物治疗12小时后,细胞愈合率仅为10%,结果如图4所示。
Transwell实验结果表明,DEX-HCI(25nmol/L)或SFC(1.25μmol/L)单独处理KYSE30细胞12h后,细胞的侵袭能力受到抑制,具有侵袭能力的细胞数量较对照组减少。联合用药增强了对KYSE30细胞侵袭能力的抑制作用,与单独用药组相比,侵袭细胞数量减少,结果如图5所示。随后,我们通过免疫荧光法检测E-Cadherin和N-Cadherin的表达,结果显示DEX-HCI和SFC能够下调KYSE30细胞中E-Cadherin和上调N-Cadherin蛋白的表达,结果如图6所示。RO8191是一种咪唑啉吡啶化合物,可激活JAK和STAT蛋白的磷酸化,从而激活JAK/STAT信号通路。为了初步探讨DEX-HCI和舒芬太尼联合给药影响KEYSE30细胞侵袭和迁移的机制,添加RO8191激活剂抵消了其对KEYSE30细胞的抑制作用,结果如图7所示。
3)DEX-HCI和SFC对KYSE30细胞糖代谢的影响
检测DEX-HCI和SFC处理后KYSE30细胞ATP水平、乳酸生成和葡萄糖摄取的变化,结果表明,与对照组相比,DEX-HCI组、SFC组和联合组的KYSE30细胞ATP水平、乳酸生成和葡萄糖摄取均降低。与DEX-HCI和SFC组相比,联合组显示KYSE30细胞的ATP水平、乳酸生成和葡萄糖摄取降低,结果如图8所示。与右美托咪定和舒芬太尼共给药组相比,在KYSE30中加入RO8191激活剂后,KEYSE30细胞的葡萄糖、ATP和乳酸含量增加,结果如图9所示。
4)DEX-HCI和SFC对KYSE30细胞相关蛋白的影响
我们证明DEX-HCI和SFC抑制KYSE30细胞的增殖、迁移和侵袭,并降低其ATP水平、乳酸生成和葡萄糖摄取。为了研究其作用机制,我们采用Western blot检测STAT3/JAK/HIF-α通路相关、侵袭相关和糖酵解相关标记蛋白的表达。结果表明,DEX-HCI和SFC可降低KYSE30细胞基质金属蛋白酶2(MMP2)、团块金属蛋白酶9(MMP9)、N-cadherin、己糖激酶2(HK2)和乳酸脱氢酶A(LDHA)蛋白的表达水平,上调Ecadherin蛋白的表达。右美托咪定与SFC联用增强了上述蛋白的调控作用,结果如图10所示。DEX-HCI和SFC可以抑制p-STAT3和p-JAK蛋白的表达水平,药物联合使用增强了这种抑制作用,但不影响STAT3和JAK蛋白的表达水平,结果如图11所示。
为了进一步确定DEX-HCI和SFC是否通过STAT3/JAK/HIF-α轴影响KYSE30细胞糖代谢和侵袭,我们通过添加RO8191诱导STAT3/JAK磷酸化进行了反向验证实验。结果显示,RO8191抵消了DEX-HCI和SFC对STAT3/JAK/HIF-α信号通路的抑制作用,减弱了对糖酵解和侵袭相关标记蛋白的影响,结果如图12所示。
上述实施例的说明只是用于理解本发明的方法及其核心思想。应当指出,对于本领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也将落入本发明权利要求的保护范围内。
Claims (10)
1.α2-肾上腺素受体激动剂联合阿片受体激动剂在制备预防或治疗食管癌的药物组合物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述α2-肾上腺素受体激动剂包括右美托咪定及其药学上可接受的盐;
优选地,所述阿片受体激动剂包括阿片μ受体激动剂、阿片κ受体激动剂、阿片μ、κ受体激动剂;
优选地,所述阿片μ受体激动剂包括吗啡、芬太尼、舒芬太尼、瑞芬太尼、美沙酮、哌替啶、羟考酮及其药学上可接受的盐;
优选地,所述阿片κ受体激动剂包括纳布啡、喷他佐辛、布托啡诺、地佐辛及其药学上可接受的盐;
优选地,所述阿片μ、κ受体激动剂包括氨酚羟考酮、氨酚待因、氨酚氢可酮、氨酚曲马多、洛芬待因及其药学上可接受的盐;
优选地,所述食管癌包括食管鳞癌。
3.一种预防或治疗食管癌的药物组合物,其特征在于,所述药物组合物包括联合使用预防或治疗有效量的权利要求1或2所述的α2-肾上腺素受体激动剂与阿片受体激动剂;
优选地,所述药物组合物还包括药学上可接受的辅料;
优选地,所述辅料包括载体、辅剂、赋形剂、稀释剂或其它液体溶媒、分散助剂、悬浮助剂、表面活性剂、等渗剂、增稠剂、乳化剂、防腐剂、固体粘合剂、润滑剂。
4.α2-肾上腺素受体激动剂联合阿片受体激动剂在抑制食管癌细胞或组织增殖、侵袭、迁移、上皮-间质转化、乳酸生成、ATP生成、葡萄糖水平、糖代谢水平中的应用。
5.根据权利要求4所述的应用,其特征在于,所述应用用于与已知载体、佐剂和/或添加剂一起使用,以口服、经皮、静脉、皮下、皮内、肌肉内、直肠、阴道或舌下用药的全身给药;
优选地,所述应用用于局部应用时乳剂、软膏、糊剂、胶剂、溶液、喷雾剂、脂质体或水状胶质敷料的形式;
优选地,所述应用中所述的两种激动剂,以相对独立的配方与已知载体、佐剂和/或添加剂同时或立即连续应用,以达到一种结合的效果。
6.α2-肾上腺素受体激动剂联合阿片受体激动剂在抑制HK2和LDHA蛋白的表达水平中的应用。
7.一种抑制HK2和LDHA蛋白的表达水平的组合物,其特征在于,所述组合物包括以下组分或由以下组分组合而成:
1)第一活性成分,所述第一活性成分包括α2-肾上腺素受体激动剂;
2)第二活性成分,所述第二活性成分包括阿片受体激动剂;
优选地,所述组合物用于制备抑制食管癌细胞的药物。
8.一种非治疗目的的抑制体外细胞HK2和LDHA蛋白的表达水平的方法,其特征在于,所述方法包括使用权利要求6所述的α2-肾上腺素受体激动剂与阿片受体激动剂的步骤。
9.一种药盒,其特征在于,所述药盒包括:
(i)含有α2-肾上腺素受体激动剂的第一制剂;
(ii)含有阿片受体激动剂的第二制剂;
(iii)使用说明书;
所述第一制剂选自:右美托咪定及其药学上可接受的盐;
所述第二制剂选自:阿片μ受体激动剂、阿片κ受体激动剂、阿片μ、κ受体激动剂;
优选地,所述阿片μ受体激动剂包括吗啡、芬太尼、舒芬太尼、瑞芬太尼、美沙酮、哌替啶、羟考酮及其药学上可接受的盐;
优选地,所述阿片κ受体激动剂包括纳布啡、喷他佐辛、布托啡诺、地佐辛及其药学上可接受的盐;
优选地,所述阿片μ、κ受体激动剂包括氨酚羟考酮、氨酚待因、氨酚氢可酮、氨酚曲马多、洛芬待因及其药学上可接受的盐;
优选地,所述使用说明书中注明将所述第一制剂和第二制剂进行联用,从而治疗食管癌,或抑制食管癌组织或细胞的增殖、侵袭、迁移、上皮-间质转化、乳酸生成、ATP生成、葡萄糖水平、糖代谢水平;
优选地,所述在治疗食管癌,或抑制食管癌组织或细胞的增殖、侵袭、迁移、上皮-间质转化、乳酸生成、ATP生成、葡萄糖水平、糖代谢水平时第一制剂、第二制剂同时给药、分别给药或顺序给药。
10.一种体外非治疗性抑制食管癌细胞或组织的方法,其特征在于,所述方法包括将权利要求3所述的药物组合物或权利要求9所述的药盒施用到体外食管癌细胞或组织上的步骤;
优选地,所述抑制具体包括抑制食管癌组织或细胞的增殖、侵袭、迁移、上皮-间质转化、乳酸生成、ATP生成、葡萄糖水平、糖代谢水平。
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