NF-κB在大黄素增强胰腺癌吉西他滨化疗敏感性中的作用  被引量:6

Role of nuclear factor-κB on emodin-induced sensitization of pancreatic cancer to gemcitabine

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作  者:刘岸[1] 胡云双[2] 王兆洪[1] 唐莉莉[2] 柯品妤[2] 林胜璋[1] 

机构地区:[1]温州医学院附属第二医院,浙江温州325027 [2]温州医学院,浙江温州325000

出  处:《药学学报》2011年第2期146-152,共7页Acta Pharmaceutica Sinica

基  金:浙江省自然科学基金资助项目(Y2080708);浙江省中医药管理局重点项目(2008ZA015)

摘  要:为探讨大黄素增强胰腺癌吉西他滨化疗敏感性的作用及其机制,本研究诱导建立耐100 nmol·L-1吉西他滨的人胰腺癌SW1990细胞株(SW1990/GZ),在体外实验中,应用CCK-8法检测细胞增殖活性;流式细胞术检测细胞凋亡;凝胶电泳迁移率实验(EMSA)检测细胞中NF-κB活性;Western blotting检测细胞中蛋白表达水平;在体内实验中,建立裸鼠胰腺癌原位移植模型;免疫组织化学法检测肿瘤组织中蛋白表达。结果表明,大黄素预处理可显著增强吉西他滨对胰腺癌细胞的生长抑制和诱导凋亡作用;大黄素联合吉西他滨可显著抑制胰腺癌原位移植瘤生长;大黄素还可下调体内外胰腺癌中NF-κB及其调控蛋白Bcl-2和Survivin的表达。提示NF-κB在大黄素增敏胰腺癌吉西他滨化疗中具有重要意义。In view of gemcitabine resistance has limited clinical activity of gemcitabine as a cellulotoxic drug in pancreatic cancer patients,this study is designed to investigate the effect of emodin on the sensitivity of pancreatic cancer to gemcitabine as well as its mechanism.After gemcitabine-resistant pancreatic cancer cell line(SW1990/GZ) was established by escalating doses of gemcitabine serially in pancreatic cancer cell line(SW1990).The cellular proliferation was detected by cell counting kit-8(CCK-8) assay.Flow cytometry(FCM) was used to determine apoptosis of pancreatic cancer cells.The activity of NF-κB in pancreatic cancer cells was measured by electrophoretic mobility shift assay(EMSA).Western blotting was used to detect the protein expression of Bcl-2 and Survivin in SW1990/GZ cells.Metastatic model simulating human pancreatic cancer was established by orthotopic implantation of histologically intact human tumor tissue into pancreatic wall of nude mice.Also,immunohistochemistry was used to detect the positive expression of Ki-67,NF-κB,Bcl-2 and Survivin in the tumors.The results show that pretreatment of cells with emodin followed by gemcitabine induced a higher percentage of growth inhibition and apoptosis of pancreatic cancer cells than that of gemcitabine alone.In addition to in vitro results,emodin in combination with gemcitabine is much more effective as an antitumor agent compared to either agent alone in the orthotopic tumor model.Further study showed that the emodin with or without gemcitabine significantly down-regulates NF-κB and its regulated molecules such as Bcl-2 and Survivin proteins both in vitro and in vivo.It is concluded that inactivation of NF-κB signaling pathway by emodin resulting in the chemosensitization of pancreatic cancer to gemcitabine,which is likely to be an important and novel strategy for the treatment of pancreatic cancer.

关 键 词:NF-ΚB 大黄素 吉西他滨 胰腺肿瘤 耐药性 

分 类 号:R963[医药卫生—微生物与生化药学] R979.1[医药卫生—药理学]

 

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