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增免抑瘤方对顺铂耐药卵巢癌裸鼠耐药相关基因HIF-1α、Glut1、MDR1、P-gp表达的影响
引用本文:李久现,张勤华,胡欣欣,齐聪.增免抑瘤方对顺铂耐药卵巢癌裸鼠耐药相关基因HIF-1α、Glut1、MDR1、P-gp表达的影响[J].上海中医药杂志,2012(1):61-64.
作者姓名:李久现  张勤华  胡欣欣  齐聪
作者单位:上海中医药大学;上海中医药大学附属曙光医院
基金项目:国家自然科学基金资助项目(30873280);上海市重点学科建设项目(S30303)
摘    要:目的研究增免抑瘤方(ZMYL)对顺铂耐药卵巢癌裸鼠耐药调控基因HIF-1α、Glut1、MDR1、P-gp表达的影响。方法采用顺铂耐药人卵巢癌细胞株COC1/DDP构建裸鼠皮下移植瘤模型,随机分为对照组,中药高、中、低剂量组,顺铂组(DDP),联合组(DDP联合中药),各组给予相应干预措施共3周。定期测量瘤体最大、最小径线,绘制肿瘤生长曲线,给药结束后处死裸鼠,剥取瘤体计算瘤重及抑瘤率,免疫组化测定瘤体HIF-1α、Glut1的表达,定量RT-PCR测定瘤体MDR1、P-gp的表达。结果①抑瘤率:联合组抑瘤率最高,达(59.26±6.86)%,与其他各组比较差异均有统计学意义(P<0.01);中药各剂量组均有一定的抑瘤作用,抑瘤率低于顺铂组(P<0.01)。②免疫组化结果:联合组HIF-1α的表达最低(P<0.01);中药高、中剂量组HIF-1α的表达较顺铂组降低(P<0.01);低剂量组与之比较差异无统计学意义(P>0.05)。联合组以及中药高剂量组Glut1的表达低于顺铂组(P<0.01);中剂量组与之比较差异无统计学意义(P>0.05);低剂量组高于顺铂组(P<0.05),但与对照组比较差异无统计学意义(P>0.05)。③定量RT-PCR结果:顺铂组MDR1、P-gp的表达较对照组升高(P<0.01);联合组以及中药各剂量组MDR1、P-gp的表达较顺铂组降低(P<0.01)。结论增免抑瘤方辅助化疗可逆转耐药卵巢癌裸鼠对顺铂的耐药性,增强其抑瘤作用;其作用机制可能通过下调瘤体内缺氧标记物Glut1、HIF-1α的表达,下调多药耐药基因MDR1、P-gp的表达,从缺氧介导的"药泵"耐药机制途径改善卵巢癌化疗耐药。

关 键 词:卵巢癌  顺铂耐药  中药  HIF-1α  Glut1  MDR1  P-gp

Effects of "Zengmian Yiliu Decoction" on expression of resistance related genes HIF-1α,Glut1,MDR1,P-gp in nude mice with Cisplatin-resistant ovarian cancer
LI Jiu-xian,ZHANG Qin-hua,HU Xin-xin,QI Cong.Effects of "Zengmian Yiliu Decoction" on expression of resistance related genes HIF-1α,Glut1,MDR1,P-gp in nude mice with Cisplatin-resistant ovarian cancer[J].Shanghai Journal of Traditional Chinese Medicine,2012(1):61-64.
Authors:LI Jiu-xian  ZHANG Qin-hua  HU Xin-xin  QI Cong
Institution:1.Class 2008 Doctoral Candidate,Shanghai University of Traditional Chinese Medicine;2.Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine
Abstract:Objective To study the effect of "Zengmian Yiliu Decoction" on expression of resistance related genes HIF-1α,Glut1,MDR1 and P-gp in nude mice with Cisplatin-resistant ovarian cancer.Methods Using the cisplatin resistant ovarian cancer cell line COC1/DDP to build the model of ovarian cancer subcutaneous tumor in nude mice.The mice were randomized into six groups: control group,herb groups(high,medium and low dose),cisplatin group(DDP) and combined group(DDP combined with herbs),intervened with drug for three weeks,measured the maximum and minimum tumor diameter on a regular basis,making the tumor growth curve.After administration,mice were sacrificed to measure the tumor weight and calculate inhibition rate,determining the expression of HIF-1α and Glut1 by immunohistochemical method,to determine the expression of MDR1 and P-gp by Quantitative RT-PCR.Results ①Inhibition rate: The inhibition rate in combined group was highest,(59.26±6.86)%,compared with other groups,there was a significant difference(P<0.01).There was certain inhibitory effect in each herb group,but inhibition rate was lower than cisplatin group(P<0.01).②Immunohistochemical results: The expression of HIF-1α in combined group was lowest(P<0.01);expression of HIF-1α reduced in herb high and medium dose groups compared with cisplatin group(P<0.01);low dose group with no significant difference(P>0.05).The expressions of Glut1 in combined group and herb high dose group were lower than that in cisplatin group(P<0.01);there was no significant difference between medium dose group and cisplatin group(P>0.05);low-dose group was higher than cisplatin group(P<0.05),but compared with the control group there was no significant difference(P>0.05).③Quantitative RT-PCR results: The expressions of MDR1 and P-gp in cisplatin group were higher than that in control group(P<0.01);the expressions of MDR1 and P-gp in combined group and herb groups were lower than that in cisplatin group(P<0.01).Conclusion "Zengmian Yiliu Decoction" with chemotherapy can reverse the cisplatin-resistance in nude mice with resistant ovarian cancer,and enhance its inhibitory effect.The mechanism is to down regulate the expressions of MDR1 and P-gp by down regulating the expressions of Glut1 and HIF-1α to improve the chemotherapy-resistance in ovarian cancer from hypoxia-mediated "drug pump" mechanism.
Keywords:ovarian cancer  cisplatin resistance  herb  HIF-1α  Glut1  MDR1  P-gp
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