环氧合酶-2/5-脂氧合酶抑制剂对酒精相关性口腔癌的抑制作用  

Inhibitory Effect of Cox-2/5-Lox Inhibitors on the Ethanol-related Oral Carcinogenesis in Mice

作　　者：王欣 刘丽霞 曹涛[1] 樊虹 张琳[1] 李艳萍[1] WANG Xin;LIU Li-xia;CAO Tao;FAN Hong;ZHANG Lin;LI Yan-ping(School of Stomatology,Harbin Medical University,Harbin,Heilongjiang,150001,China;Community Health Center ofLaoshan District,Qingdao,Shandong,266100,China)

机构地区：[1]哈尔滨医科大学附属口腔医学院牙体牙髓病科,黑龙江哈尔滨150001 [2]山东省青岛市崂山区社区卫生服务中心,山东青岛266100

出　　处：《现代生物医学进展》2019年第6期1044-1048,1063,共6页Progress in Modern Biomedicine

基　　金：黑龙江省自然科学基金青年科学基金项目(QC2012C092)

摘　　要：目的:分析和比较选择性环氧合酶-2 (Cox-2)抑制剂塞来昔布、5-脂氧合酶(5-Lox)抑制剂齐留通及Cox/5-Lox双酶抑制剂利克飞龙对酒精相关性口腔癌的抑制作用。方法:选择66只C57BL/6小鼠,分为阴性对照组、模型组(4NQO组)、阳性对照组、齐留通干预组、塞来昔布干预组和利克飞龙干预组。阴性对照组不做任何处理,其余各组饮用50μg/m L四硝基喹啉-1-氧化物(4NQO)溶液16周后,阳性对照组及各干预组以8%酒精溶液代替饮用水喂养8周,同时开始分别用三蒸水和同等药量的齐留通、塞来昔布、利克飞龙(100 mg·kg-1·d-1)灌胃8周;于24周处死动物,取舌行组织病理学观察、BrdU免疫组化染色、蛋白质印迹法(Western-blot)检测舌组织中5-Lox、Cox-2蛋白的表达。结果:饮用酒精后,口腔癌发生率从16.7%增加到58.3%,5-Lox、Cox-2蛋白表达显著增加癌组织中BrdU阳性率显著升高。齐留通干预后,口腔癌发生率(41.7%)显著降低,5-Lox表达显著减少,Cox-2表达显著增加,Brd U阳性率显著降低;塞来昔布干预后,口腔癌发生率(50.0%)显著降低,Cox-2表达显著减少,5-Lox表达显著增加,BrdU阳性率显著降低;利克飞龙干预后,口腔癌发生率(25%),Brd U阳性率与阳性对照组、齐留通干预组和塞来昔布干预组相比均显著降低,5-Lox、Cox-2蛋白表达比阳性对照组显著减少(P<0.05)。结论:酒精促进口腔癌变的过程可能与5-Lox和Cox-2的表达上调关系密切;齐留通和塞来昔布可以分别抑制5-Lox和Cox-2活性,使口腔癌的发生率显著降低;利克飞龙对口腔癌的抑制作用优于齐留通和塞来昔布。Objective:To study the inhibitory effect of Zileuton(a specific 5-Lox inhibitor),Celecoxib(a specific Cox-2 inhibitor)and Licofelone(a dual Cox/5-Lox inhibitor)on ethanol-related oral carcinogenesis in mice.Methods:66 C57 BL/6 mice were divided into 6 groups randomly.The negative control group(n=6)was not treated,the remaining mice were divided into 5 groups(12 mice in each group)and treated with 4 NQO in their drinking water at a concentration of 50μg/m L for a period of 16 weeks.Then the mice in 4 NQO control group was not treated afterwards,those in the other 4 groups were received by distilled water,Zileuton,Celecoxib and Licofelone respectively.At week 24,all the animals were sacrificed.The tongue was harvested and examined for histopathology,immunohistochemical and western blotting.Results:Long-term 8%ethanol consumption significantly increased the oral SCC incidence(from 16.7%to 58.3%),5-Lox and Cox-2 protein expression,and the Brd U-labeling index The oral SCC incidence and the BrdU-labeling index in Zileuton group,Celecoxib group and Licofelone group were significantly lower than those in positive control group.The oral SCC incidence and the Brd U-labeling index in Licofelone group were significantly lower than those in Zileuton group or Celecoxib group.5-Lox and Cox-2 protein expression in Licofelone group,5-Lox protein expression in Zileuton group and Cox-2 protein expression in celecoxib group were significantly lower than those in positive control group.Cox-2 protein expression in Zileuton group and 5-Lox protein expression in Celecoxib group were significantly higher than those in positive control group.Conclusions:Ethanol can promot 4 NQO-induced oral carcinogenesis through activation of the 5-Lox and Cox-2 pathway of arachidonic acid metabolism.Zileuton and Celecoxib have inhibitory effects against ethanol-related oral carcinogenesis and such inhibition may be related to the suppression of 5-Lox and Cox-2 protein expression.The inhibitory effect of Licofelone is better than that of Zileuton and C

关 键 词：齐留通 塞来昔布 利克飞龙 口腔癌 5-脂氧合酶 环氧合酶-2 酒精 

分 类 号：R-33[医药卫生] R739.8