甲基莲心碱抗肿瘤药理作用及其分子机制研究进展
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摘要
目的:了解甲基莲心碱(Nef)抗肿瘤的药理作用及其分子机制研究进展,为该生物碱的进一步开发利用提供依据。方法:以"甲基莲心碱""肿瘤""Neferine""Anti-tumor""Cancer"等中英文为关键词,在中国知网、万方数据、PubMed等数据库中组合查询发表于2000年-2018年9月的文献,对Nef抗肿瘤的药理作用及分子机制进行综述。结果:共检索到文献84篇,其中有效文献34篇。结果与结论:Nef是一种提取自莲子心的双苄基异喹啉类生物碱,具有多重抗肿瘤药理活性。Nef可通过诱导肿瘤细胞凋亡、阻滞肿瘤细胞周期、影响肿瘤细胞的自噬过程,从而抑制肿瘤细胞增殖;可通过提高肿瘤细胞对化疗药物的敏感性(如影响肿瘤细胞线粒体功能、抑制炎症相关信号通路、阻碍上皮间质性转化进程、协同抗肿瘤药物)、降低化疗药物(如阿霉素、顺铂等)的毒性起到减毒增效的作用。近年来,有关Nef的基础研究逐渐增多,但主要集中在体外分子机制研究,而基于体内实验的安全性评价及药理研究十分缺乏。多数研究关注于Nef在细胞水平内与炎症通路、自噬过程、氧化应激反应的关系,但对引起这类反应的上游肿瘤相关靶点的研究仍有待深入开展。此外,Nef要从基础研究到临床应用仍有相当的距离,如何优化药物剂型、提高有效成分生物利用度,是今后亟需解决的问题。
引文
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[2]欧明,王宁生.中药及其制剂不良反应大典[M].沈阳:辽宁科学技术出版社,2002:144.
[3]杨永,王笑民.试论“心神”与癌毒[J].中医杂志,2017,58(1):76-78.
[4]JUNG HA,JIN SE,CHOI RJ,et al.Anti-amnesic activity of neferine with antioxidant and anti-inflammatory capacities,as well as inhibition of ChEs and BACE1[J].Life Sci,2010,87(13/14):420-430.
[5]SUGIMOTO Y,FURUTANI S,NISHIMURA K,et al.Antidepressant-like effects of neferine in the forced swimming test involve the serotonin1A(5-HT1A)receptor in mice[J].Eur J Pharmacol,2010,634(1/2/3):62-67.
[6]CHEN MS,ZHANG JH,WANG JL,et al.Anti-fibrotic effects of neferine on carbon tetrachloride-induced hepatic fibrosis in mice[J].Am J Chin Med,2015,43(2):231-240.
[7]ZHOU YJ,XIANG JZ,YUAN H,et al.Neferine exerts its antithrombotic effect by inhibiting platelet aggregation and promoting dissociation of platelet aggregates[J].Thromb Res,2013,132(2):202-210.
[8]PAN Y,CAI B,WANG K,et al.Neferine enhances insulin sensitivity in insulin resistant rats[J].J Ethnopharmacol,2009,124(1):98-102.
[9]GUAN G,HAN H,YANG Y,et al.Neferine prevented hyperglycemia-induced endothelial cell apoptosis through suppressing ROS/Akt/NF-kappaB signal[J].Endocrine,2014,47(3):764-771.
[10]ZHOU H,JIANG H,YAO T,et al.Fragmentation study on the phenolic alkaloid neferine and its analogues with anti-HIV activities by electrospray ionization tandem mass spectrometry with hydrogen/deuterium exchange and its application for rapid identification of in vitro microsomal metabolites of neferine[J].Rapid Commun Mass Spectrom,2007,21(13):2120-2128.
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[14]ZHANG X,LIU Z,XU B,et al.Neferine,an alkaloid ingredient in lotus seed embryo,inhibits proliferation of human osteosarcoma cells by promoting p38 MAPK-mediated p21 stabilization[J].Eur J Pharmacol,2012,677(1/2/3):47-54.
[15]曹建平,夏大静.自噬与肿瘤关系研究新进展[J].浙江大学学报(医学版),2015,44(2):204-210.
[16]陈雪,钟莉莉,王洪冰,等.自噬性细胞死亡研究进展[J].现代肿瘤医学,2019,27(6):1072-1075.
[17]POORNIMA P,WENG C F,PADMA V V.Neferine from Nelumbo nucifera induces autophagy through the inhibition of PI3K/Akt/mTOR pathway and ROS hyper generation in A549 cells[J].Food Chem,2013,141(4):3598-3605.
[18]XU L,ZHANG X,LI Y,et al.Neferine induces autophagy of human ovarian cancer cells via p38 MAPK/JNK activation[J].Tumour Biol,2016,37(7):8721-8729.
[19]XU T,SINGH D,LIU J,et al.Neferine,is not inducer but blocker for macroautophagic flux targeting on lysosome malfunction[J].Biochem Biophys Res Commun,2018,495(1):1516-1521.
[20]周静.莲心碱抑制自噬降解及调节线粒体分裂增敏乳腺癌化疗的分子机制[D].重庆:第三军医大学,2015.
[21]徐珊,徐昌芬.肿瘤多药耐药性发生机制及中药逆转作用的研究进展[J].中国肿瘤生物治疗杂志,2006,13(6):404-411.
[22]CAO JG,TANG XQ,SHI SH.Multidrug resistance reversal in human gastric carcinoma cells by neferine[J].World J Gastroenterol,2004,10(20):3062-3064.
[23]POORNIMA P,KUMAR VB,WENG CF,et al.Doxorubicin induced apoptosis was potentiated by neferine in human lung adenocarcima,A549 cells[J].Food Chem Toxicol,2014.DOI:10.1016/j.fct.2014.03.008.
[24]SIVALINGAM KS,PARAMASIVAN P,WENG CF,et al.Neferine potentiates the antitumor effect of cisplatin in human lung adenocarcinoma cells via a mitochondria-mediated apoptosis pathway[J].J Cell Biochem,2017,118(9):2865-2876.
[25]DENG G,ZENG S,MA J,et al.The anti-tumor activities of neferine on cell invasion and oxaliplatin sensitivity regulated by EMT via Snail signaling in hepatocellular carcinoma[J].Sci Rep,2017.DOI:10.1038/srep41616.
[26]张永飞,崔久嵬.化疗药物所致心脏毒性的研究进展[J].中国肿瘤临床,2018,45(24):1243-1247.
[27]PRIYA LB,BASKARAN R,HUANG CY,et al.Neferine ameliorates cardiomyoblast apoptosis induced by doxorubicin:possible role in modulating NADPH oxidase/ROS-mediated NFkappaB redox signaling cascade[J].Sci Rep,2017.DOI:10.1038/s41598-017-12060-9.
[28]BHARATHI PRIYA L,BASKARAN R,HUANG CY,et al.Neferine modulates IGF-1R/Nrf2 signaling in doxorubicin treated H9c2 cardiomyoblasts[J].J Cell Biochem,2018,119(2):1441-1452.
[29]杨慧海,王露露,范超,等.中药有效成分减轻顺铂肾毒性研究进展[J].上海中医药杂志,2017,51(5):98-101.
[30]LI H,TANG Y,WEN L,et al.Neferine reduces cisplatin-induced nephrotoxicity by enhancing autophagy via the AMPK/mTOR signaling pathway[J].Biochem Biophys Res Commun,2017,484(3):694-701.
[31]ZHAO L,WANG X,CHANG Q,et al.Neferine,a bisbenzylisoquinline alkaloid attenuates bleomycin-induced pulmonary fibrosis[J].Eur J Pharmacol,2010,627(1/2/3):304-312.
[32]HANAHAN D,WEINBERG RA.Hallmarks of cancer:the next generation[J].Cell,2011,144(5):646-674.
[33]DE PALMA M,BIZIATO D,PETROVA TV.Microenvironmental regulation of tumour angiogenesis[J].Nat Rev Cancer,2017,17(8):457-474.
[34]ZHANG Q,LI Y,MIAO C,et al.Anti-angiogenesis effect of neferine via regulating autophagy and polarization of tumor-associated macrophages in high-grade serous ovarian carcinoma[J].Cancer Lett,2018.DOI:10.1016/j.canlet.2018.05.049.
[2]欧明,王宁生.中药及其制剂不良反应大典[M].沈阳:辽宁科学技术出版社,2002:144.
[3]杨永,王笑民.试论“心神”与癌毒[J].中医杂志,2017,58(1):76-78.
[4]JUNG HA,JIN SE,CHOI RJ,et al.Anti-amnesic activity of neferine with antioxidant and anti-inflammatory capacities,as well as inhibition of ChEs and BACE1[J].Life Sci,2010,87(13/14):420-430.
[5]SUGIMOTO Y,FURUTANI S,NISHIMURA K,et al.Antidepressant-like effects of neferine in the forced swimming test involve the serotonin1A(5-HT1A)receptor in mice[J].Eur J Pharmacol,2010,634(1/2/3):62-67.
[6]CHEN MS,ZHANG JH,WANG JL,et al.Anti-fibrotic effects of neferine on carbon tetrachloride-induced hepatic fibrosis in mice[J].Am J Chin Med,2015,43(2):231-240.
[7]ZHOU YJ,XIANG JZ,YUAN H,et al.Neferine exerts its antithrombotic effect by inhibiting platelet aggregation and promoting dissociation of platelet aggregates[J].Thromb Res,2013,132(2):202-210.
[8]PAN Y,CAI B,WANG K,et al.Neferine enhances insulin sensitivity in insulin resistant rats[J].J Ethnopharmacol,2009,124(1):98-102.
[9]GUAN G,HAN H,YANG Y,et al.Neferine prevented hyperglycemia-induced endothelial cell apoptosis through suppressing ROS/Akt/NF-kappaB signal[J].Endocrine,2014,47(3):764-771.
[10]ZHOU H,JIANG H,YAO T,et al.Fragmentation study on the phenolic alkaloid neferine and its analogues with anti-HIV activities by electrospray ionization tandem mass spectrometry with hydrogen/deuterium exchange and its application for rapid identification of in vitro microsomal metabolites of neferine[J].Rapid Commun Mass Spectrom,2007,21(13):2120-2128.
[11]POORNIMA P,QUENCY RS,PADMA VV.Neferine induces reactive oxygen species mediated intrinsic pathway of apoptosis in HepG2 cells[J].Food Chem,2013,136(2):659-667.
[12]YOON JS,KIM HM,YADUNANDAM AK,et al.Neferine isolated from Nelumbo nucifera enhances anti-cancer activities in Hep3B cells:molecular mechanisms of cell cycle arrest,ER stress induced apoptosis and anti-angiogenic response[J].Phytomedicine,2013,20(11):1013-1022.
[13]高燕,林莉萍,丁健.细胞周期调控的研究进展[J].生命科学,2005,17(4):318-322.
[14]ZHANG X,LIU Z,XU B,et al.Neferine,an alkaloid ingredient in lotus seed embryo,inhibits proliferation of human osteosarcoma cells by promoting p38 MAPK-mediated p21 stabilization[J].Eur J Pharmacol,2012,677(1/2/3):47-54.
[15]曹建平,夏大静.自噬与肿瘤关系研究新进展[J].浙江大学学报(医学版),2015,44(2):204-210.
[16]陈雪,钟莉莉,王洪冰,等.自噬性细胞死亡研究进展[J].现代肿瘤医学,2019,27(6):1072-1075.
[17]POORNIMA P,WENG C F,PADMA V V.Neferine from Nelumbo nucifera induces autophagy through the inhibition of PI3K/Akt/mTOR pathway and ROS hyper generation in A549 cells[J].Food Chem,2013,141(4):3598-3605.
[18]XU L,ZHANG X,LI Y,et al.Neferine induces autophagy of human ovarian cancer cells via p38 MAPK/JNK activation[J].Tumour Biol,2016,37(7):8721-8729.
[19]XU T,SINGH D,LIU J,et al.Neferine,is not inducer but blocker for macroautophagic flux targeting on lysosome malfunction[J].Biochem Biophys Res Commun,2018,495(1):1516-1521.
[20]周静.莲心碱抑制自噬降解及调节线粒体分裂增敏乳腺癌化疗的分子机制[D].重庆:第三军医大学,2015.
[21]徐珊,徐昌芬.肿瘤多药耐药性发生机制及中药逆转作用的研究进展[J].中国肿瘤生物治疗杂志,2006,13(6):404-411.
[22]CAO JG,TANG XQ,SHI SH.Multidrug resistance reversal in human gastric carcinoma cells by neferine[J].World J Gastroenterol,2004,10(20):3062-3064.
[23]POORNIMA P,KUMAR VB,WENG CF,et al.Doxorubicin induced apoptosis was potentiated by neferine in human lung adenocarcima,A549 cells[J].Food Chem Toxicol,2014.DOI:10.1016/j.fct.2014.03.008.
[24]SIVALINGAM KS,PARAMASIVAN P,WENG CF,et al.Neferine potentiates the antitumor effect of cisplatin in human lung adenocarcinoma cells via a mitochondria-mediated apoptosis pathway[J].J Cell Biochem,2017,118(9):2865-2876.
[25]DENG G,ZENG S,MA J,et al.The anti-tumor activities of neferine on cell invasion and oxaliplatin sensitivity regulated by EMT via Snail signaling in hepatocellular carcinoma[J].Sci Rep,2017.DOI:10.1038/srep41616.
[26]张永飞,崔久嵬.化疗药物所致心脏毒性的研究进展[J].中国肿瘤临床,2018,45(24):1243-1247.
[27]PRIYA LB,BASKARAN R,HUANG CY,et al.Neferine ameliorates cardiomyoblast apoptosis induced by doxorubicin:possible role in modulating NADPH oxidase/ROS-mediated NFkappaB redox signaling cascade[J].Sci Rep,2017.DOI:10.1038/s41598-017-12060-9.
[28]BHARATHI PRIYA L,BASKARAN R,HUANG CY,et al.Neferine modulates IGF-1R/Nrf2 signaling in doxorubicin treated H9c2 cardiomyoblasts[J].J Cell Biochem,2018,119(2):1441-1452.
[29]杨慧海,王露露,范超,等.中药有效成分减轻顺铂肾毒性研究进展[J].上海中医药杂志,2017,51(5):98-101.
[30]LI H,TANG Y,WEN L,et al.Neferine reduces cisplatin-induced nephrotoxicity by enhancing autophagy via the AMPK/mTOR signaling pathway[J].Biochem Biophys Res Commun,2017,484(3):694-701.
[31]ZHAO L,WANG X,CHANG Q,et al.Neferine,a bisbenzylisoquinline alkaloid attenuates bleomycin-induced pulmonary fibrosis[J].Eur J Pharmacol,2010,627(1/2/3):304-312.
[32]HANAHAN D,WEINBERG RA.Hallmarks of cancer:the next generation[J].Cell,2011,144(5):646-674.
[33]DE PALMA M,BIZIATO D,PETROVA TV.Microenvironmental regulation of tumour angiogenesis[J].Nat Rev Cancer,2017,17(8):457-474.
[34]ZHANG Q,LI Y,MIAO C,et al.Anti-angiogenesis effect of neferine via regulating autophagy and polarization of tumor-associated macrophages in high-grade serous ovarian carcinoma[J].Cancer Lett,2018.DOI:10.1016/j.canlet.2018.05.049.
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