24-羟基-人参二醇的抗癌作用及基于分子对接的机制
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摘要
目的:为研究人参皂苷20(S)-达玛-20,25-环氧-3β,12β,24α-三醇(24-OH-PD)对多种癌细胞的增殖抑制及诱导凋亡作用并探讨其作用机制。方法:采用噻唑蓝(MTT)比色法或Cell Titer Glo发光试验检测24-OH-PD在不同质量浓度(12. 5,25,50,100 mg·L~(-1)),不同作用时间(24,48,72 h)下对CCRF-CEM,Jeko-1,M14,MD-MBA-231癌细胞的增殖抑制作用,并与20(R)-Rg3,20(S)-Rh_2进行比较。采用流式细胞术检测24-OH-PD对以上4种癌细胞的凋亡诱导作用。采用药物设计平台薛定谔Maestro 6. 7软件对癌症相关的40种蛋白与24-OH-PD进行分子对接研究。结果:24-OH-PD对4种癌细胞均具有明显的细胞活性抑制作用,且具有时间、剂量依赖性。24-OH-PD对CCRF-CEM,Jeko-1,M14,MD-MBA-231细胞作用48 h时半抑制浓度(IC50)分别为25. 36,39. 29,21. 74,19. 35 mg·L~(-1),与20(S)-Rh_2作用效果相似(IC50分别为23. 35,65. 79,18. 95,19. 67 mg·L~(-1));远远强于20(R)-Rg3,仅对Jeko-1细胞有抑制作用(IC5049. 5 mg·L~(-1))。磷脂结合蛋白V/碘化吡啶(Annexin V/PI)双染实验结果显示,24-OH-PD对4种细胞均具有不同程度的促凋亡作用(P <0. 05),且具有剂量依赖关系。分子对接实验表明32个癌症相关蛋白中有11个能够与24-OH-PD对接成功,包括嘌呤核苷磷酸化酶(PNP),蛋白络氨酸激酶,蛋白激酶C(PKC),B淋巴细胞瘤基因-2(Bcl-2),B淋巴细胞瘤基因-xl (Bcl-xl),含半胱氨酸的天冬氨酸蛋白水解酶-8等,表明24-OH-PD的抗肿瘤作用可能与直接作用于这些蛋白相关。结论:人参皂苷24-OH-PD对CCRF-CEM,M14,MD-MBA-231,Jeko-1癌细胞具有增殖抑制作用,其机制可能与PNP,PKC等蛋白相关;同时24-OH-PD还具有诱导癌细胞凋亡的作用,机制可能与Bcl-2,Bcl-xl等蛋白相关。
Objective: To investigate the effect of ginsenoside 20( S),25-epoxydammarane-3β,12β,24α-triol( 24-OH-panaxadiol,24-OH-PD) on inhibiting proliferation and inducing apoptosis of tumor cells,and explore its mechanism of action. Method: The inhibitory effect of 24-OH-PD( 12. 5,25,50,100 mg·L~(-1)) on proliferation of CCRF-CEM,M14,MD-MBA-231 and Jeko-1 cells with different treatment periods( 24,48,72 h)was evaluated by methylthiazolyldiphenyl-tetrazolium bromide( MTT) assay and CellTiter Glo test,and the results were then compared with 20( R)-Rg3 and 20( S)-Rh_2. Flow cytometry was used to detect cell apoptosis caused by 24-OH-PD. Besides,the potential anticancer mechanism was studied by docking analysis with 40 cancer related proteins and 24-OH-PD by using drug design platform Schrodinger Maestro 6. 7 Software. Result: 24-OHPD inhibited the proliferation of all the 4 cancer cell lines significantly in a time and dosage dependent manner. The IC50 value of 24-OH-PD on CCRF-CEM,Jeko-1,M14,and MD-MBA-231 cell lines was 25. 36,39. 29,21. 74,and 19. 35 mg·L~(-1),respectively,similar to 20( S)-Rh_2( IC5023. 35,65. 79,18. 95,19. 67 mg·L~(-1)) and much better than 20( R)-Rg3( only effective for Jeko-1 cells,IC5049. 5 mg·L~(-1)). Annexin V/PI double staining experiment showed that 24-OH-PD could also induce apoptosis of the 4 kinds of cancer cells( P < 0. 05) in a dose-dependent manner. In the molecular docking test,24-OH-PD was docked successfully with 11 tumor related proteins,including purine nucleoside phosphorylase( PNP),protein tyrosine kinase,protein kinase C( PKC),B-cell lymphoma-2( Bcl-2),B-cell lymphoma-xl( Bcl-xl) and Caspase-8 et al,which demonstrated that the antitumor effect of 24-OH-PD may be related to the direct effects on these proteins. Conclusion: 24-OH-PD could inhibit cell proliferation and induce apoptosis for CCRF-CEM,M14,MD-MBA-231 and Jeko-1 cell lines,which may through directly acting on Bcl-2,Bcl-xl,and other proteins.
Objective: To investigate the effect of ginsenoside 20( S),25-epoxydammarane-3β,12β,24α-triol( 24-OH-panaxadiol,24-OH-PD) on inhibiting proliferation and inducing apoptosis of tumor cells,and explore its mechanism of action. Method: The inhibitory effect of 24-OH-PD( 12. 5,25,50,100 mg·L~(-1)) on proliferation of CCRF-CEM,M14,MD-MBA-231 and Jeko-1 cells with different treatment periods( 24,48,72 h)was evaluated by methylthiazolyldiphenyl-tetrazolium bromide( MTT) assay and CellTiter Glo test,and the results were then compared with 20( R)-Rg3 and 20( S)-Rh_2. Flow cytometry was used to detect cell apoptosis caused by 24-OH-PD. Besides,the potential anticancer mechanism was studied by docking analysis with 40 cancer related proteins and 24-OH-PD by using drug design platform Schrodinger Maestro 6. 7 Software. Result: 24-OHPD inhibited the proliferation of all the 4 cancer cell lines significantly in a time and dosage dependent manner. The IC50 value of 24-OH-PD on CCRF-CEM,Jeko-1,M14,and MD-MBA-231 cell lines was 25. 36,39. 29,21. 74,and 19. 35 mg·L~(-1),respectively,similar to 20( S)-Rh_2( IC5023. 35,65. 79,18. 95,19. 67 mg·L~(-1)) and much better than 20( R)-Rg3( only effective for Jeko-1 cells,IC5049. 5 mg·L~(-1)). Annexin V/PI double staining experiment showed that 24-OH-PD could also induce apoptosis of the 4 kinds of cancer cells( P < 0. 05) in a dose-dependent manner. In the molecular docking test,24-OH-PD was docked successfully with 11 tumor related proteins,including purine nucleoside phosphorylase( PNP),protein tyrosine kinase,protein kinase C( PKC),B-cell lymphoma-2( Bcl-2),B-cell lymphoma-xl( Bcl-xl) and Caspase-8 et al,which demonstrated that the antitumor effect of 24-OH-PD may be related to the direct effects on these proteins. Conclusion: 24-OH-PD could inhibit cell proliferation and induce apoptosis for CCRF-CEM,M14,MD-MBA-231 and Jeko-1 cell lines,which may through directly acting on Bcl-2,Bcl-xl,and other proteins.
引文
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[3]ZHANG Q,KANG X,YANG B,et al.Antiangiogenic effect of capecitabine combined with ginsenoside Rg3on breast cancer in mice[J].Cancer Biother Radiopharm,2008,23(5):647-653.
[4]LIU T,ZHAO L,ZHANG Y,et al.Ginsenoside 20(S)-Rg3targets HIF-1αto block hypoxia-induced epithelial-mesenchymal transition in ovarian cancer cells[J].PLo S One,2014,9(9):e103887.
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[6]权恺,刘群,李萍,等.人参皂苷抗癌活性的最新研究进展[J].医学研究生学报,2015,28(4):427-431.
[7]ZHENG Q,LI Z,LIU J,et al.Two new dammaranetype triterpene sapogenins from Chinese red ginseng[J].Nat Prod Res,2016,30(1):95-99.
[8]WANG Z,Pratts S G,ZHANG H,et al.Treg depletion in non-human primates using a novel diphtheria toxin-based anti-human CCR4 immunotoxin[J].Mol Oncol,2016,10(4):553-565.
[9]Stamos J,Sliwkowski M X,Eigenbrot C.Structure of the EGF receptor kinase domain alone and in complex with a4-anilinoquinazoline inhibitor[J].J Biol Chem,2002,75(36):2091-2092.
[10]Sarkar J,Nandy S K,Chowdhury A,et al.Inhibition of MMP-9 by green tea catechins and prediction of their interaction by molecular docking analysis[J].Biomed Pharmacother,2016,84:340-347.
[11]Revelant G,Al-Lakkis-Wehbe M,Schmitt M,et al.Exploring S1 plasticity and probing S1’subsite of mammalian Aminopeptidase N/CD13 with highly potent and selective aminobenzosuberone inhibitors[J].Bioorgan Med Chem,2015,23(13):3192-3207.
[12]Sansen S,Yano J K,Reynald R L,et al.Adaptations for the oxidation of polycyclic aromatic hydrocarbons exhibited by the structure of human P450 1A2[J].JBiol Chem,2007,282(19):14348-14355.
[13]Vinh N B,Devine S M,Munoz L,et al.Design,synthesis,and biological evaluation of tetra-substituted thiophenes as inhibitors of p38αMAPK[J].Chemistryopen,2015,4(1):56-64.
[14]Singh S,Das T,Awasthi M,et al.DNA topoisomerasedirected anticancerous alkaloids:ADMET-based screening,molecular docking,and dynamics simulation[J].Biotechnol Appl Bioc,2015,63(1):125-137.
[15]Sartaj T,Mehvash Z,Mohd A,et al.Synthesis and characterization of Cu(Ⅱ)-based anticancer chemotherapeutic agent targeting topoisomerase Iα:in vitro DNA binding,p BR322 cleavage,molecular docking studies and cytotoxicity against human cancer cell lines[J].Eur J Med Chem,2014,74(5):509-523.
[16]Gogoi D,Baruah V J,Chaliha A K,et al.3Dpharmacophore-based virtual screening,docking and density functional theory approach towards the discovery of novel human epidermal growth factor receptor-2(HER2)[J].J Theor Biol,2016,411:68-80.
[17]WANG Y,CHENG F X,YUAN X L,et al.Dihydropyrazole derivatives as telomerase inhibitors:structure-based design,synthesis,SAR and anticancer evaluation in vitro and in vivo[J].Euro J Med Chem,2016,112:231-251.
[18]Dufe V T,Ingner D,Heby O,et al.A structural insight into the inhibition of human and Leishmania donovani ornithine decarboxylases by 1-amino-oxy-3-aminopropane[J].Biochem J,2007,405(2):261-268.
[19]苏敬雷.中药穿心莲和冬凌草的计算药理学研究[D].郑州:郑州大学,2015.
[20]Fatima S,Jatavath M B,Bathini R,et al.Multiple receptor conformation docking,dock pose clustering and3D QSAR studies on human poly(ADP-ribose)polymerase-1(PARP-1)inhibitors[J].J Recept Sig Transd,2014,34(5):417-430.
[21]Abdel Latif N A,Batran R Z,Khedr M A,et al.3-Substituted-4-hydroxycoumarin as a new scaffold with potent CDK inhibition and promising anticancer effect:Synthesis,molecular modeling and QSAR studies[J].Bioorg Chem,2016,67:116-129.
[22]Sathishkumar N,Sathiyamoorthy S,Ramya M,et al.Molecular docking studies of anti-apoptotic Bcl-2,Bclxl,and MCL-1 proteins with ginsenosides from Panax ginseng[J].J Enzyme Inhib Med Chem,2012,27(5):685-692.
[23]Pottel J,Therrien E,Gleason J L,et al.Docking ligands into flexible and solvated macromolecules.6.development and application to the docking of HDACs and other Zinc metalloenzymes inhibitors[J].J Cheml Inf Model,2013,54(1):254-65.
[24]Balachandran C,Sangeetha B,Duraipandiyan V,et al.A flavonoid isolated from Streptomyces sp.(ERINLG-4)induces apoptosis in human lung cancer A549 cells through p53 and cytochrome C release caspase dependant pathway[J].Chem-Biol Interact,2014,224:24-35.
[25]Leong K H,Looi C Y,Loong X M,et al.Cycloart-24-ene-26-ol-3-one,a new cycloartane isolated from leaves of aglaia exima triggers tumour Necrosis factor-receptor1-mediated Caspase-dependent apoptosis in colon cancer cell line[J].PLo S One,2016,11(4):e0152652.
[26]Saloahen O M H,Tochowicz A,Pozzi C,et al.Hotspots in an obligate homodimeric anticancer target.Structural and functional effects of interfacial mutations in human thymidylate synthase[J].J Med Chem,2015,58(8):3572-3581.
[27]WANG Z,WANG N,HAN S,et al.Dietary compound isoliquiritigenin inhibits breast cancer neoangiogenesis via VEGF/VEGFR-2 signaling pathway[J].PLo S One,2013,8(7):e68566.
[28]ZHU W,WANG W,XU S,et al.Design,synthesis,and docking studies of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors[J].Bioorgan Med Chem,2016,24(8):1749-1756.
[29]Naresh K M,Thunuguntla V B S C,Veeramachaneni GK,et al.Molecular characterization of human ABHD2as TAG lipase and ester hydrolase[J].Bioscience Rep,2016,36(4):1-11.
[30]Keerthy H K,Mohan C D,Siveen K S,et al.Novel synthetic biscoumarins target tumor necrosis factor-αin hepatocellular carcinoma in vitro and in vivo[J].J Biol Chem,2014,289(46):31879-31890.
[31]Kadioglu O,CAO J,Saeed M E M,et al.Targeting epidermal growth factor receptors and downstream signaling pathways in cancer by phytochemicals[J].Target Oncol,2015,10(3):337-353.
[32]戴国梁,马世堂,刘史佳,等.二咖啡酰奎宁酸与人血浆阿司匹林酯酶的分子对接[J].中成药,2014,36(9):1901-1905.
[33]Kojima S,Chiyomaru T,Kawakami K,et al.Tumour suppressors miR-1 and miR-133a target the oncogenic function of purine nucleoside phosphorylase(PNP)in prostate cancer[J].Brit J Cancer,2011,106(2):405-413.
[34]Popovich D G,Kitts D D.Structure-function relationship exists for ginsenosides in reducing cell proliferation and inducing apoptosis in the human leukemia(THP-1)cell line[J].Arch Biochem Biophys,2002,406(1):1-8.
[35]DONG H,BAI L P,WONG V K,et al.The in vitro structure-related anti-cancer activity of ginsenosides and their derivatives[J].Molecules,2011,16(12):10619-10630.
[36]刘存,刘丽娟,周超,等.基于“蛋白质相互作用网络-分子对接技术-体外实验”三维模式分析青黛对慢性粒细胞白血病的作用机制[J].中国实验方剂学杂志,2017,23(21):206-211.
[37]Arpaia E,Benveniste P,Di Cristofano A,et al.Mitochondrial basis for immune deficiency:evidence from purine nucleoside phosphorylase-deficient mice[J].J Exp Med,2000,191(12):2197-2208.
[38]Ravandi F,Gandhi V.Novel purine nucleoside analogues for T-cell-lineage acute lymphoblastic leukaemia and lymphoma[J].Expert Opin Investig Drugs,2006,15(12):1601-1613.
[39]吴洁,倪沛洲,凌霞.蛋白激酶C的研究进展[J].中国药物化学杂志,2001,11(3):182-186.
[40]You W K,Sennino B,Williamson C W,et al.VEGFand c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer[J].Cancer Res,2011,71(14):OF1-11.
[41]Min J K,Kim J H,Cho Y L,et al.20(S)-Ginsenoside Rg3prevents endothelial cell apoptosis via inhibition of a mitochondrial caspase pathway[J].Biochem Biophy Res Co,2006,349(3):987-994.
[42]刘德明,周春燕,吴嘉思,等.大黄素通过线粒体通路诱导Hep G2细胞凋亡[J].中国实验方剂学杂志,2018,24(3):104-108.
[2]Ota T,Maeda M,Odashima S,et al.G1 phase-specific suppression of the Cdk2 activity by ginsenoside Rh2in cultured murine cells[J].Life Sci,1997,60(2):PL39-44.
[3]ZHANG Q,KANG X,YANG B,et al.Antiangiogenic effect of capecitabine combined with ginsenoside Rg3on breast cancer in mice[J].Cancer Biother Radiopharm,2008,23(5):647-653.
[4]LIU T,ZHAO L,ZHANG Y,et al.Ginsenoside 20(S)-Rg3targets HIF-1αto block hypoxia-induced epithelial-mesenchymal transition in ovarian cancer cells[J].PLo S One,2014,9(9):e103887.
[5]WU R,RU Q,CHEN L,et al.Stereospecificity of ginsenoside Rg3in the promotion of cellular immunity in Hepatoma H22-bearing mice[J].J Food Sci,2014,79(7):1430-1435.
[6]权恺,刘群,李萍,等.人参皂苷抗癌活性的最新研究进展[J].医学研究生学报,2015,28(4):427-431.
[7]ZHENG Q,LI Z,LIU J,et al.Two new dammaranetype triterpene sapogenins from Chinese red ginseng[J].Nat Prod Res,2016,30(1):95-99.
[8]WANG Z,Pratts S G,ZHANG H,et al.Treg depletion in non-human primates using a novel diphtheria toxin-based anti-human CCR4 immunotoxin[J].Mol Oncol,2016,10(4):553-565.
[9]Stamos J,Sliwkowski M X,Eigenbrot C.Structure of the EGF receptor kinase domain alone and in complex with a4-anilinoquinazoline inhibitor[J].J Biol Chem,2002,75(36):2091-2092.
[10]Sarkar J,Nandy S K,Chowdhury A,et al.Inhibition of MMP-9 by green tea catechins and prediction of their interaction by molecular docking analysis[J].Biomed Pharmacother,2016,84:340-347.
[11]Revelant G,Al-Lakkis-Wehbe M,Schmitt M,et al.Exploring S1 plasticity and probing S1’subsite of mammalian Aminopeptidase N/CD13 with highly potent and selective aminobenzosuberone inhibitors[J].Bioorgan Med Chem,2015,23(13):3192-3207.
[12]Sansen S,Yano J K,Reynald R L,et al.Adaptations for the oxidation of polycyclic aromatic hydrocarbons exhibited by the structure of human P450 1A2[J].JBiol Chem,2007,282(19):14348-14355.
[13]Vinh N B,Devine S M,Munoz L,et al.Design,synthesis,and biological evaluation of tetra-substituted thiophenes as inhibitors of p38αMAPK[J].Chemistryopen,2015,4(1):56-64.
[14]Singh S,Das T,Awasthi M,et al.DNA topoisomerasedirected anticancerous alkaloids:ADMET-based screening,molecular docking,and dynamics simulation[J].Biotechnol Appl Bioc,2015,63(1):125-137.
[15]Sartaj T,Mehvash Z,Mohd A,et al.Synthesis and characterization of Cu(Ⅱ)-based anticancer chemotherapeutic agent targeting topoisomerase Iα:in vitro DNA binding,p BR322 cleavage,molecular docking studies and cytotoxicity against human cancer cell lines[J].Eur J Med Chem,2014,74(5):509-523.
[16]Gogoi D,Baruah V J,Chaliha A K,et al.3Dpharmacophore-based virtual screening,docking and density functional theory approach towards the discovery of novel human epidermal growth factor receptor-2(HER2)[J].J Theor Biol,2016,411:68-80.
[17]WANG Y,CHENG F X,YUAN X L,et al.Dihydropyrazole derivatives as telomerase inhibitors:structure-based design,synthesis,SAR and anticancer evaluation in vitro and in vivo[J].Euro J Med Chem,2016,112:231-251.
[18]Dufe V T,Ingner D,Heby O,et al.A structural insight into the inhibition of human and Leishmania donovani ornithine decarboxylases by 1-amino-oxy-3-aminopropane[J].Biochem J,2007,405(2):261-268.
[19]苏敬雷.中药穿心莲和冬凌草的计算药理学研究[D].郑州:郑州大学,2015.
[20]Fatima S,Jatavath M B,Bathini R,et al.Multiple receptor conformation docking,dock pose clustering and3D QSAR studies on human poly(ADP-ribose)polymerase-1(PARP-1)inhibitors[J].J Recept Sig Transd,2014,34(5):417-430.
[21]Abdel Latif N A,Batran R Z,Khedr M A,et al.3-Substituted-4-hydroxycoumarin as a new scaffold with potent CDK inhibition and promising anticancer effect:Synthesis,molecular modeling and QSAR studies[J].Bioorg Chem,2016,67:116-129.
[22]Sathishkumar N,Sathiyamoorthy S,Ramya M,et al.Molecular docking studies of anti-apoptotic Bcl-2,Bclxl,and MCL-1 proteins with ginsenosides from Panax ginseng[J].J Enzyme Inhib Med Chem,2012,27(5):685-692.
[23]Pottel J,Therrien E,Gleason J L,et al.Docking ligands into flexible and solvated macromolecules.6.development and application to the docking of HDACs and other Zinc metalloenzymes inhibitors[J].J Cheml Inf Model,2013,54(1):254-65.
[24]Balachandran C,Sangeetha B,Duraipandiyan V,et al.A flavonoid isolated from Streptomyces sp.(ERINLG-4)induces apoptosis in human lung cancer A549 cells through p53 and cytochrome C release caspase dependant pathway[J].Chem-Biol Interact,2014,224:24-35.
[25]Leong K H,Looi C Y,Loong X M,et al.Cycloart-24-ene-26-ol-3-one,a new cycloartane isolated from leaves of aglaia exima triggers tumour Necrosis factor-receptor1-mediated Caspase-dependent apoptosis in colon cancer cell line[J].PLo S One,2016,11(4):e0152652.
[26]Saloahen O M H,Tochowicz A,Pozzi C,et al.Hotspots in an obligate homodimeric anticancer target.Structural and functional effects of interfacial mutations in human thymidylate synthase[J].J Med Chem,2015,58(8):3572-3581.
[27]WANG Z,WANG N,HAN S,et al.Dietary compound isoliquiritigenin inhibits breast cancer neoangiogenesis via VEGF/VEGFR-2 signaling pathway[J].PLo S One,2013,8(7):e68566.
[28]ZHU W,WANG W,XU S,et al.Design,synthesis,and docking studies of phenylpicolinamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors[J].Bioorgan Med Chem,2016,24(8):1749-1756.
[29]Naresh K M,Thunuguntla V B S C,Veeramachaneni GK,et al.Molecular characterization of human ABHD2as TAG lipase and ester hydrolase[J].Bioscience Rep,2016,36(4):1-11.
[30]Keerthy H K,Mohan C D,Siveen K S,et al.Novel synthetic biscoumarins target tumor necrosis factor-αin hepatocellular carcinoma in vitro and in vivo[J].J Biol Chem,2014,289(46):31879-31890.
[31]Kadioglu O,CAO J,Saeed M E M,et al.Targeting epidermal growth factor receptors and downstream signaling pathways in cancer by phytochemicals[J].Target Oncol,2015,10(3):337-353.
[32]戴国梁,马世堂,刘史佳,等.二咖啡酰奎宁酸与人血浆阿司匹林酯酶的分子对接[J].中成药,2014,36(9):1901-1905.
[33]Kojima S,Chiyomaru T,Kawakami K,et al.Tumour suppressors miR-1 and miR-133a target the oncogenic function of purine nucleoside phosphorylase(PNP)in prostate cancer[J].Brit J Cancer,2011,106(2):405-413.
[34]Popovich D G,Kitts D D.Structure-function relationship exists for ginsenosides in reducing cell proliferation and inducing apoptosis in the human leukemia(THP-1)cell line[J].Arch Biochem Biophys,2002,406(1):1-8.
[35]DONG H,BAI L P,WONG V K,et al.The in vitro structure-related anti-cancer activity of ginsenosides and their derivatives[J].Molecules,2011,16(12):10619-10630.
[36]刘存,刘丽娟,周超,等.基于“蛋白质相互作用网络-分子对接技术-体外实验”三维模式分析青黛对慢性粒细胞白血病的作用机制[J].中国实验方剂学杂志,2017,23(21):206-211.
[37]Arpaia E,Benveniste P,Di Cristofano A,et al.Mitochondrial basis for immune deficiency:evidence from purine nucleoside phosphorylase-deficient mice[J].J Exp Med,2000,191(12):2197-2208.
[38]Ravandi F,Gandhi V.Novel purine nucleoside analogues for T-cell-lineage acute lymphoblastic leukaemia and lymphoma[J].Expert Opin Investig Drugs,2006,15(12):1601-1613.
[39]吴洁,倪沛洲,凌霞.蛋白激酶C的研究进展[J].中国药物化学杂志,2001,11(3):182-186.
[40]You W K,Sennino B,Williamson C W,et al.VEGFand c-Met blockade amplify angiogenesis inhibition in pancreatic islet cancer[J].Cancer Res,2011,71(14):OF1-11.
[41]Min J K,Kim J H,Cho Y L,et al.20(S)-Ginsenoside Rg3prevents endothelial cell apoptosis via inhibition of a mitochondrial caspase pathway[J].Biochem Biophy Res Co,2006,349(3):987-994.
[42]刘德明,周春燕,吴嘉思,等.大黄素通过线粒体通路诱导Hep G2细胞凋亡[J].中国实验方剂学杂志,2018,24(3):104-108.