中药复方多靶点逆转肺癌化疗多药耐药机制效应的研究进展
|
摘要
多药耐药是目前肺癌化疗失败的主要原因,如何预防或逆转肺癌多耐药仍然是亟待解决的临床棘手问题。中医辨证理论指导下的中药复方在肺癌多药耐药研究中日益受到重视。以现代医学肿瘤多药耐药机制研究为依据,文章归纳发现:中药复方可以通过下调膜转运蛋白,降低肿瘤细胞解毒修复功能,影响信号转导凋亡调控基因、细胞周期、细胞外基质、线粒体相关分子调控效应及抑制或干扰内质网应激等机制发挥抗耐药效应,体现了中药复方干预肺癌耐药的高效、低毒、多靶点优势。相关研究为肺癌耐药的临床干预和科研提供了参考。
Multi-drug resistance(MDR) is the main cause of chemotherapy failure in lung cancer. How to prevent or reverse the MDR of lung cancer is still a clinically difficult problem to be solved. Traditional Chinese medicine compound prescription under the guidance of TCM syndrome differentiation theory has received increasing attention in the study of MDR of lung cancer. Based on the research of MDR mechanism of modern medical tumors, this paper concluded that Chinese herbal compound prescription could down-regulate membrane transport protein, reduce tumor cell detoxification and repair function, affect signal transduction apoptosis regulatory genes, cell cycle, extracellular matrix, mitochondria related molecular regulation effects and inhibition or interference with endoplasmic reticulum stress to play a role in anti-drug resistance. It reflected the highefficiency, low-toxicity and multi-target advantages of traditional Chinese medicine compound prescription intervention in lung cancer resistance. Related researches provided a reference for clinical intervention and research on lung cancer resistance.
Multi-drug resistance(MDR) is the main cause of chemotherapy failure in lung cancer. How to prevent or reverse the MDR of lung cancer is still a clinically difficult problem to be solved. Traditional Chinese medicine compound prescription under the guidance of TCM syndrome differentiation theory has received increasing attention in the study of MDR of lung cancer. Based on the research of MDR mechanism of modern medical tumors, this paper concluded that Chinese herbal compound prescription could down-regulate membrane transport protein, reduce tumor cell detoxification and repair function, affect signal transduction apoptosis regulatory genes, cell cycle, extracellular matrix, mitochondria related molecular regulation effects and inhibition or interference with endoplasmic reticulum stress to play a role in anti-drug resistance. It reflected the highefficiency, low-toxicity and multi-target advantages of traditional Chinese medicine compound prescription intervention in lung cancer resistance. Related researches provided a reference for clinical intervention and research on lung cancer resistance.
引文
[1]Li Y,Yuan H,Yang K,et al.The structure and functions of P-glycoprotein.Curr Med Chem,2010,17(8):786-800
[2]季旭明,欧阳兵,王春燕,等.温下方逆转A549/DDP细胞的多药耐药及对膜表面蛋白表达的影响.中国药物与临床,2006,6(12):885-888
[3]吴智春,于华芸,季旭明,等.温下方联合顺铂对A549/DDP裸鼠移植瘤的抑制作用及对药物转运蛋白表达的影响.中华临床医师杂志(电子版),2011,5(20):5884-5888
[4]曹勇,熬杰男,马民,等.补肾化瘀解毒方荷瘤药物血清对A549/DDP耐药逆转作用的研究.陕西中医,2004,25(7):663-665
[5]曹勇,张丹,郑广娟,等.补肾化瘀解毒方药对肺癌耐药细胞的耐药逆转及机制研究.山东中医杂志,2004,23(2):100-103
[6]曹勇,李亮,钟安朴,等.补肾化瘀解毒方药物血清对肺癌A549/DDP细胞的耐药逆转及MRP表达的影响.中国病理生理杂志,2008,24(3):591-593
[7]刘明,薛芳芳.化疗联合补中益气汤加减治疗中晚期非小细胞肺癌30例.湖南中医杂志,2013,29(5):42-44
[8]井欢,唐莹,于丹,等.补中益气汤含药血清同siRNA对A549/DDP细胞MRP表达影响的比较.中国实验方剂学杂志,2014,20(8):150-153
[9]高原,王莹,陈奇,等.补中益气汤对肺腺癌荷瘤裸鼠移植瘤的抑瘤作用及MRP蛋白表达影响的研究.时珍国医国药,2016,27(8):1796-1799
[10]井欢,于丹,唐莹,等.补中益气汤对A549/DDP肺癌荷瘤BALB/c小鼠耐药相关蛋白MRP表达的影响.解剖科学进展,2014,20(1):28-30
[11]于丹,于宁,王雨,等.补中益气汤对肺腺癌A549/DDP荷瘤小鼠LRP蛋白影响的研究.中华中医药杂志,2014,29(5):1412-1415
[12]高原,王哲,陈奇,等.补中益气汤对肺腺癌顺铂耐药细胞株与顺铂敏感细胞株荷瘤BALB/c小鼠移植瘤P-gp表达的影响.中国老年学杂志,2016,36(13):3089-3091
[13]董昀,张铭,沙慧芳,等.中药七叶灵颗粒逆转肺腺癌细胞耐药机制研究.中国中医基础医学杂志,2014,20(5):678-682
[14]田菲,贾文娟,邢秀玲,等.扶正合剂含药血清对肺癌细胞生长及耐药基因表达的影响.中医研究,2007,20(8):20-22
[15]孙建立,孙玺媛,刘嘉湘.金复康口服液对耐药人肺腺癌A549/DDP膜转运蛋白LRP MRP mRNA表达的影响.辽宁中医药大学学报,2009,11(7):210-213
[16]邹珊珊,徐榕,何琪杨.复方中药紫龙金克服肿瘤细胞多药耐药性的机制.中国中西医结合杂志,2010,30(6):601-604
[17]张莹,贾英杰,李小江,等.消岩汤对耐顺铂人肺腺癌A549/DDP细胞多药耐药基因调控作用的研究.药物评价研究,2014,37(6):507-510
[18]Backos D S,Franklin C C,Reigan P.The role of glutathione in brain tumor drug resistance.Biochem Pharmacol,2012,83(8):1005-1012
[19]Min Y,Mao C Q,Chen S,et al.Combating the drug resistance of cisplatin using a platinum prodrug based delivery system.Angew Chem Int Ed Engl,2012,51(27):6742-6747
[20]Nitiss J L.Targeting DNA topoisomeraseⅡin cancer chemotherapy.Nat Rev Cancer,2009,9(5):338-350
[21]欧阳兵,季旭明,王春燕,等.温下方含药血清对A549/DDP细胞内erbB-2、Topo-Ⅱ表达及铂含量的影响.新中医,2008,40(5):101-102
[22]季旭明,江涛,欧阳兵,等.温下方含药血清对肺腺癌耐药细胞内GSH、GST-π的影响.山东中医药大学学报,2010,34(1):67-69
[23]井欢,于丹,唐莹,等.补中益气汤对A549/DDP动物模型实体瘤中耐药相关酶GST和TopoⅡ表达的影响.解剖科学进展,2014,20(3):249-252
[24]梁昆,徐立群,薛兴阳,等.参慈胶囊影响人肺腺癌A549/DDP裸鼠体内多药耐药DNA损伤修复的研究.云南中医学院学报,2016,39(3):1-4
[25]Niture S K,Jaiswal A K.Nrf2-induced antiapoptotic Bcl-x L protein enhances cell survival and drug resistance.Free Radic Biol Med,2013,57:119-131
[26]Park E,Gang E J,Hsieh Y T,et al.Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia.Blood,2011,118(8):2191-2199
[27]Ding Z Y,Liu G H,Olsson B,et al.Upregulation of the antiapoptotic factor Livin contributes to cisplatin resistance in colon cancer cells.Tumour Biol,2013,34(2):683-693
[28]熊英,刘春英,王淳.参芪扶正注射液对人肺腺癌耐药细胞株A549/DDP的增敏作用.上海中医药大学学报,2016,30(4):52-56
[29]季旭明,欧阳兵,吴智春,等.温下方含药血清诱导A549/DDP细胞凋亡及对Bcl-2, Bax, p53蛋白表达的影响.中国实验诊断学,2011,17(12):123-126
[30]井欢,于丹,唐莹,等.补中益气汤对A549/DDP肺腺癌耐药动物模型中凋亡相关信号分子caspase-9的影响.解剖科学进展,2014,20(2):134-136,141
[31]Zhao L J,Xu H,Qu J W,et al.Modulation of drug resistance in ovarian cancer cells by inhibition of protein kinase C-alpha(PKC-α)with small interference RNA(siRNA)agents.Asian Pac J Cancer Prev,2012,13(8):3631-3636
[32]Cassinelli G,Zuco V,Gatti L,et al.Targeting the akt kinase to modulate survival,invasiveness and drug resistance of cancer cells.Curr Med Chem,2013,20(15):1923-1945
[33]Yang H Y,Zhao L,Yang Z,et al.Oroxylin A reverses multidrug resistance of human hepatoma BEL7402/5-FU cells via downregulation of P-glycoprotein expression by inhibiting NF-κB signaling pathway.Mol Carcinog,2012,51(2):185-195
[34]杨佩颖,许文婷,刘宏根,等.消岩汤对A549/DDP细胞自噬及耐药蛋白的影响研究.天津中医药,2016,33(6):358-362
[35]张恩欣,周岱翰,侯超.益气除痰方通过抑制Akt信号通路诱导顺铂耐药肺癌细胞凋亡的作用及分子机制研究.中药新药与临床药理,2016,27(3):365-371
[36]刘亚莉,易佳丽,王莹,等.补中益气汤含药血清对A549/DDP细胞PI3K/AKT信号转导通路影响的实验研究.中国医科大学学报,2014,43(1):14-18
[37]刘亚莉,王莹,易佳丽,等.补中益气汤含药血清对人肺腺癌A549/DDP细胞耐药作用的影响.中国病理生理杂志,2014,30(2):223-238
[38]易佳丽,王莹,井欢,等.补中益气汤含药血清逆转人肺腺癌耐药细胞株A549/DDP耐顺铂作用及对Survivin表达的影响.中国中西医结合杂志,2014,34(10):1250-1255
[39]史妍婷,井欢,王莹,等.补中益气汤含药血清逆转A549/DDP的顺铂耐药及对mTOR表达的影响.中国实验方剂学杂志,2013,19(9):215-219
[40]刘亚莉,唐莹,易佳丽,等.补中益气汤对肺腺癌顺铂耐药细胞株裸鼠移植瘤作用及其机制的研究.时珍国医国药,2014,25(9):2091-2093
[41]刘亚莉,王莹,易佳丽,等.补中益气汤对肺腺癌顺铂耐药细胞株移植瘤裸鼠脾、胃和肺中PI3K和AKT表达的影响.中国中药杂志,2014,39(10):1869-1873
[42]孙玺媛,孙建立.益气养阴方逆转人肺腺癌A549/DDP多药耐药机理.实用肿瘤学杂志,2009,23(1):26-28,34
[43]曹勇,钟安朴,陈璐,等.补肾化瘀解毒复方含药血清对肺癌A549/DDP耐药细胞周期的影响.中医杂志,2008,49(6):546-549
[44]张恩欣,周岱翰,侯超.益气除痰方含药血清对顺铂耐药肺癌细胞增殖和细胞周期的影响.山东医药,2016,56(6):13-15
[45]周琳,于丹,刘春英.补中益气汤含药血清干预上皮间质转化对A549/DDP细胞凋亡的影响.中华中医药杂志,2017,32(4):1473-1477
[46]唐莹,郭倩,于宁,等.补中益气汤含药血清对TGF-β1介导的A549细胞中Vimentin及GST-π蛋白表达的影响.中华中医药杂志,2016,31(5):1737-1740
[47]徐萌,朱新海,盛良翮.益气养阴方干预肺癌化疗耐药的线粒体及半胱天冬酶机制.中药材,2008,31(9):1396-1399
[48]徐萌,张国军,潘兰红,等.益气扶正中药对肺癌耐药调控的线粒体相关分子效应.中国肿瘤临床,2010,37(13):725-728
[49]Xuemei Li,Kezhong Zhang,Zihai Li.Unfolded protein response in cancer:the physician’s perspective.J Hematol Oncol,2011,4:8
[50]Healy S J,Gorman A M,Mousavi-Shafaei P,et al.Targeting the endoplasmic reticulum-stress response as an anticancer strategy.Eur J Pharmacol,2009,625:234-246
[51]Li J,Lee A S.Stress induction of GRP78/Bip and its role in cancer.Curr Mol Med,2006,6(1):45-54
[52]Ramsay R G,Ciznadija D,Mantamadiotis T,et al.Expression of stress response protein glucose regulated protein-78 mediated by c-Myb.Int J Biochem Cell Biol,2005,37(6):1254-1268
[53]Koomagi R,Mattern J,Volm M.Glucose-related protein(GRP78)and its relation-ship to the drug-resistance proteins P170,GSTpi,LRP56 and angiogenesis in non-small cell lung carcinomas.Anticancer Res,1999,19(5B):4333-4336
[54]李元滨,林丽珠,杨建猛,等.益气除痰方对耐顺铂肺癌移植瘤生长及下调UPR诱导细胞凋亡的研究.中华中医药杂志,2014,29(12):3906-3910
[55]李元滨,林丽珠.岭南肺癌辨治思路探析.中华中医药杂志,2014,29(1):141-143
[56]王超,李元滨,刘友章.基于“大气论”的岭南重症肌无力病机阐述.中华中医药杂志,2012,27(5):1370-1372
[2]季旭明,欧阳兵,王春燕,等.温下方逆转A549/DDP细胞的多药耐药及对膜表面蛋白表达的影响.中国药物与临床,2006,6(12):885-888
[3]吴智春,于华芸,季旭明,等.温下方联合顺铂对A549/DDP裸鼠移植瘤的抑制作用及对药物转运蛋白表达的影响.中华临床医师杂志(电子版),2011,5(20):5884-5888
[4]曹勇,熬杰男,马民,等.补肾化瘀解毒方荷瘤药物血清对A549/DDP耐药逆转作用的研究.陕西中医,2004,25(7):663-665
[5]曹勇,张丹,郑广娟,等.补肾化瘀解毒方药对肺癌耐药细胞的耐药逆转及机制研究.山东中医杂志,2004,23(2):100-103
[6]曹勇,李亮,钟安朴,等.补肾化瘀解毒方药物血清对肺癌A549/DDP细胞的耐药逆转及MRP表达的影响.中国病理生理杂志,2008,24(3):591-593
[7]刘明,薛芳芳.化疗联合补中益气汤加减治疗中晚期非小细胞肺癌30例.湖南中医杂志,2013,29(5):42-44
[8]井欢,唐莹,于丹,等.补中益气汤含药血清同siRNA对A549/DDP细胞MRP表达影响的比较.中国实验方剂学杂志,2014,20(8):150-153
[9]高原,王莹,陈奇,等.补中益气汤对肺腺癌荷瘤裸鼠移植瘤的抑瘤作用及MRP蛋白表达影响的研究.时珍国医国药,2016,27(8):1796-1799
[10]井欢,于丹,唐莹,等.补中益气汤对A549/DDP肺癌荷瘤BALB/c小鼠耐药相关蛋白MRP表达的影响.解剖科学进展,2014,20(1):28-30
[11]于丹,于宁,王雨,等.补中益气汤对肺腺癌A549/DDP荷瘤小鼠LRP蛋白影响的研究.中华中医药杂志,2014,29(5):1412-1415
[12]高原,王哲,陈奇,等.补中益气汤对肺腺癌顺铂耐药细胞株与顺铂敏感细胞株荷瘤BALB/c小鼠移植瘤P-gp表达的影响.中国老年学杂志,2016,36(13):3089-3091
[13]董昀,张铭,沙慧芳,等.中药七叶灵颗粒逆转肺腺癌细胞耐药机制研究.中国中医基础医学杂志,2014,20(5):678-682
[14]田菲,贾文娟,邢秀玲,等.扶正合剂含药血清对肺癌细胞生长及耐药基因表达的影响.中医研究,2007,20(8):20-22
[15]孙建立,孙玺媛,刘嘉湘.金复康口服液对耐药人肺腺癌A549/DDP膜转运蛋白LRP MRP mRNA表达的影响.辽宁中医药大学学报,2009,11(7):210-213
[16]邹珊珊,徐榕,何琪杨.复方中药紫龙金克服肿瘤细胞多药耐药性的机制.中国中西医结合杂志,2010,30(6):601-604
[17]张莹,贾英杰,李小江,等.消岩汤对耐顺铂人肺腺癌A549/DDP细胞多药耐药基因调控作用的研究.药物评价研究,2014,37(6):507-510
[18]Backos D S,Franklin C C,Reigan P.The role of glutathione in brain tumor drug resistance.Biochem Pharmacol,2012,83(8):1005-1012
[19]Min Y,Mao C Q,Chen S,et al.Combating the drug resistance of cisplatin using a platinum prodrug based delivery system.Angew Chem Int Ed Engl,2012,51(27):6742-6747
[20]Nitiss J L.Targeting DNA topoisomeraseⅡin cancer chemotherapy.Nat Rev Cancer,2009,9(5):338-350
[21]欧阳兵,季旭明,王春燕,等.温下方含药血清对A549/DDP细胞内erbB-2、Topo-Ⅱ表达及铂含量的影响.新中医,2008,40(5):101-102
[22]季旭明,江涛,欧阳兵,等.温下方含药血清对肺腺癌耐药细胞内GSH、GST-π的影响.山东中医药大学学报,2010,34(1):67-69
[23]井欢,于丹,唐莹,等.补中益气汤对A549/DDP动物模型实体瘤中耐药相关酶GST和TopoⅡ表达的影响.解剖科学进展,2014,20(3):249-252
[24]梁昆,徐立群,薛兴阳,等.参慈胶囊影响人肺腺癌A549/DDP裸鼠体内多药耐药DNA损伤修复的研究.云南中医学院学报,2016,39(3):1-4
[25]Niture S K,Jaiswal A K.Nrf2-induced antiapoptotic Bcl-x L protein enhances cell survival and drug resistance.Free Radic Biol Med,2013,57:119-131
[26]Park E,Gang E J,Hsieh Y T,et al.Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia.Blood,2011,118(8):2191-2199
[27]Ding Z Y,Liu G H,Olsson B,et al.Upregulation of the antiapoptotic factor Livin contributes to cisplatin resistance in colon cancer cells.Tumour Biol,2013,34(2):683-693
[28]熊英,刘春英,王淳.参芪扶正注射液对人肺腺癌耐药细胞株A549/DDP的增敏作用.上海中医药大学学报,2016,30(4):52-56
[29]季旭明,欧阳兵,吴智春,等.温下方含药血清诱导A549/DDP细胞凋亡及对Bcl-2, Bax, p53蛋白表达的影响.中国实验诊断学,2011,17(12):123-126
[30]井欢,于丹,唐莹,等.补中益气汤对A549/DDP肺腺癌耐药动物模型中凋亡相关信号分子caspase-9的影响.解剖科学进展,2014,20(2):134-136,141
[31]Zhao L J,Xu H,Qu J W,et al.Modulation of drug resistance in ovarian cancer cells by inhibition of protein kinase C-alpha(PKC-α)with small interference RNA(siRNA)agents.Asian Pac J Cancer Prev,2012,13(8):3631-3636
[32]Cassinelli G,Zuco V,Gatti L,et al.Targeting the akt kinase to modulate survival,invasiveness and drug resistance of cancer cells.Curr Med Chem,2013,20(15):1923-1945
[33]Yang H Y,Zhao L,Yang Z,et al.Oroxylin A reverses multidrug resistance of human hepatoma BEL7402/5-FU cells via downregulation of P-glycoprotein expression by inhibiting NF-κB signaling pathway.Mol Carcinog,2012,51(2):185-195
[34]杨佩颖,许文婷,刘宏根,等.消岩汤对A549/DDP细胞自噬及耐药蛋白的影响研究.天津中医药,2016,33(6):358-362
[35]张恩欣,周岱翰,侯超.益气除痰方通过抑制Akt信号通路诱导顺铂耐药肺癌细胞凋亡的作用及分子机制研究.中药新药与临床药理,2016,27(3):365-371
[36]刘亚莉,易佳丽,王莹,等.补中益气汤含药血清对A549/DDP细胞PI3K/AKT信号转导通路影响的实验研究.中国医科大学学报,2014,43(1):14-18
[37]刘亚莉,王莹,易佳丽,等.补中益气汤含药血清对人肺腺癌A549/DDP细胞耐药作用的影响.中国病理生理杂志,2014,30(2):223-238
[38]易佳丽,王莹,井欢,等.补中益气汤含药血清逆转人肺腺癌耐药细胞株A549/DDP耐顺铂作用及对Survivin表达的影响.中国中西医结合杂志,2014,34(10):1250-1255
[39]史妍婷,井欢,王莹,等.补中益气汤含药血清逆转A549/DDP的顺铂耐药及对mTOR表达的影响.中国实验方剂学杂志,2013,19(9):215-219
[40]刘亚莉,唐莹,易佳丽,等.补中益气汤对肺腺癌顺铂耐药细胞株裸鼠移植瘤作用及其机制的研究.时珍国医国药,2014,25(9):2091-2093
[41]刘亚莉,王莹,易佳丽,等.补中益气汤对肺腺癌顺铂耐药细胞株移植瘤裸鼠脾、胃和肺中PI3K和AKT表达的影响.中国中药杂志,2014,39(10):1869-1873
[42]孙玺媛,孙建立.益气养阴方逆转人肺腺癌A549/DDP多药耐药机理.实用肿瘤学杂志,2009,23(1):26-28,34
[43]曹勇,钟安朴,陈璐,等.补肾化瘀解毒复方含药血清对肺癌A549/DDP耐药细胞周期的影响.中医杂志,2008,49(6):546-549
[44]张恩欣,周岱翰,侯超.益气除痰方含药血清对顺铂耐药肺癌细胞增殖和细胞周期的影响.山东医药,2016,56(6):13-15
[45]周琳,于丹,刘春英.补中益气汤含药血清干预上皮间质转化对A549/DDP细胞凋亡的影响.中华中医药杂志,2017,32(4):1473-1477
[46]唐莹,郭倩,于宁,等.补中益气汤含药血清对TGF-β1介导的A549细胞中Vimentin及GST-π蛋白表达的影响.中华中医药杂志,2016,31(5):1737-1740
[47]徐萌,朱新海,盛良翮.益气养阴方干预肺癌化疗耐药的线粒体及半胱天冬酶机制.中药材,2008,31(9):1396-1399
[48]徐萌,张国军,潘兰红,等.益气扶正中药对肺癌耐药调控的线粒体相关分子效应.中国肿瘤临床,2010,37(13):725-728
[49]Xuemei Li,Kezhong Zhang,Zihai Li.Unfolded protein response in cancer:the physician’s perspective.J Hematol Oncol,2011,4:8
[50]Healy S J,Gorman A M,Mousavi-Shafaei P,et al.Targeting the endoplasmic reticulum-stress response as an anticancer strategy.Eur J Pharmacol,2009,625:234-246
[51]Li J,Lee A S.Stress induction of GRP78/Bip and its role in cancer.Curr Mol Med,2006,6(1):45-54
[52]Ramsay R G,Ciznadija D,Mantamadiotis T,et al.Expression of stress response protein glucose regulated protein-78 mediated by c-Myb.Int J Biochem Cell Biol,2005,37(6):1254-1268
[53]Koomagi R,Mattern J,Volm M.Glucose-related protein(GRP78)and its relation-ship to the drug-resistance proteins P170,GSTpi,LRP56 and angiogenesis in non-small cell lung carcinomas.Anticancer Res,1999,19(5B):4333-4336
[54]李元滨,林丽珠,杨建猛,等.益气除痰方对耐顺铂肺癌移植瘤生长及下调UPR诱导细胞凋亡的研究.中华中医药杂志,2014,29(12):3906-3910
[55]李元滨,林丽珠.岭南肺癌辨治思路探析.中华中医药杂志,2014,29(1):141-143
[56]王超,李元滨,刘友章.基于“大气论”的岭南重症肌无力病机阐述.中华中医药杂志,2012,27(5):1370-1372