水飞蓟宾对大鼠实验性肝癌抗肿瘤作用的研究
摘要
目的探讨水飞蓟宾(Silibinin or Silybin,SB)对诱导性大鼠肝癌模型的抗肿瘤作用及其可能机制。
方法改良法建立二乙基亚硝胺(DENA)大鼠诱导性肝癌模型,随机分为水飞蓟宾低剂量组:200μg/ml、中剂量组:l000μg/ml l、高剂量组:5000μg/ml及对照组,自由饮用水饲给药,对照组给予相同体积灭菌自来水。观测荷瘤鼠存活率,不同时期平均体重;用药8周后处死大鼠,观察肿瘤生长及转移情况,留取肝脏及双肺,量瘤重、鼠重,仔细观察有无转移结节,通过大体观察及病理切片检测肿瘤转移情况,计量平均肝重指数、肝肺平均表面结节数及肺转移率;肝脏标本及肿瘤组织通过常规HE染色进行病理形态学观察,了解肿瘤生长及转移情况;免疫组化法检测肿瘤血管生成相关蛋白缺氧诱导因子-1α(HIF-1α)、血管内皮生长因子(VEGF)、CD31,肿瘤细胞增值核抗原Ki-67及凋亡相关蛋白caspase-3的表达,CD31标记内皮细胞行肿瘤微血管记数;逆转录聚合酶链反应检测HIF-1αmRNA及VEGF mRNA水平。应用单因素方差分析、χ2检验及Kaplan-Meier法对相应资料分别进行统计学分析。
结果(1)水饲水飞蓟宾200 ppm、l000 ppm、5000 ppm三个剂量组较对照组均能显著增加荷瘤鼠的存活率(92.9%、85.7%、71.9%,对照组为69.2%)、大鼠平均肝重指数(4.56%±0.40%、4.98%±0.50%、9.28%±1.91%,对照组14.25%±3.90%),平均肝/肺表面结节数[(6.13±0.21)/(0.51.±0.21)个、(7.67±0.82)/(0.78.±0.13)个、(11.76±2.15)/(3.11.±0.37)个,对照组(19.32±3.31)/ (4.81.±0.53)个]及肺转移率(15.4%、25.0%、50%对比55.6%)降低,P值均<0.05;微血管密度值显著减少(0.56±0.11、0.62±0.18、2.31±0.64,对照组3.01±0.98),P <0.01;水飞蓟宾各剂量组较对照组肝癌组织中HIF-1α、VEGF、CD31、ki-67蛋白表达及VEGF mRNA水平均有显著下调,而caspase-3蛋白表达则有明显增加,P值均<0.01或0.05, HIF-1αmRNA水平各剂量组均较对照组则无明显差异。
结论水飞蓟宾可显著抑制肝癌的生长及转移,其可能机制如下:(1)、抗肿瘤血管生成,抑制肿瘤生长转移;(2)、通过干预细胞周期进程阻滞肿瘤细胞增殖;(3)、多步骤多途径诱导肿瘤细胞凋亡。
Objective: To investigate the anti-tumor effects of Silybinin (SB) on induced rat model of hepatocellular carcinoma (HCC) and its possible mechanism.
Methods: Diethylnitrosamine (DENA)-induced rat model of HCC was established by using a modifier method. All rats were randomly divided into SB low-dose group (200μg/ml), SB middle-dose group (1000μg/ml), SB high-dose group (5000μg/ml) and control group (equal volume of sterile water), received free drinking water mixed with the drug. During the experimental period, survival situation of rats was dynamically observed. After 8-week drug treatment, all rats were sacrificed and tumor growth and metastasis were examined. Liver and lung specimens were stained by HE to observe the pathomorphological changes as routine. The levels of hypoxia-inducible factor 1 alpha (HIF-1α), vascular endothelial growth factor (VEGF), Ki-67 and caspase-3 proteins and mRNAs were detected by immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. Additionally, one-way ANOVA,χ2 test and Kaplan-Meier method were used to statistically analyze the corresponding data.
Results: Compared with the control group (69.2%), SB-treated rats had higher survival rate (92.9%, 85.7% and 71.9%); The mean liver weight index (4.56%±0.40%、4.98%±0.50% and 9.28%±1.91%), the mean liver nodules (6.13±0.21),(7.67±0.82), (11.76±2.15); the mean lung nodules (0.51.±0.21) , (0.78±0.13), (3.11.±0.37) ; the lung metastsis rate ((15.4%、25.0% and 50%), and the intratumoral microvessel density (MVD) (0.56±0.11、0.62±0.18 and 2.31±0.64 ) were lower in rats treated with SB than those in control group, which were 14.25%±3.90%, 19.32±3.31, 4.81.±0.53 and 55.6% respectively (P <0.01 or P <0.05). HIF-1α, VEGF, and Ki67 proteins and VEGF mRNA were more obviously downregulated in SB-treated rats than those in control rats, while Caspase-3 protein was statistically increased. Moreover, the level of HIF-1αmRNA had no difference compared between SB groups and control group.
Conclusions: Silibinin can obviously inhibit tumor growth and metastasis of HCC. The possible associated mechanisms are as follows: (1) Inhibition of tumor growth and metastasis through antiangiogenesis; (2) Inhibition of tumor growth through blockage of cell proliferation; (3) Exerting antitumor effects through induction of cell apoptosis.
方法改良法建立二乙基亚硝胺(DENA)大鼠诱导性肝癌模型,随机分为水飞蓟宾低剂量组:200μg/ml、中剂量组:l000μg/ml l、高剂量组:5000μg/ml及对照组,自由饮用水饲给药,对照组给予相同体积灭菌自来水。观测荷瘤鼠存活率,不同时期平均体重;用药8周后处死大鼠,观察肿瘤生长及转移情况,留取肝脏及双肺,量瘤重、鼠重,仔细观察有无转移结节,通过大体观察及病理切片检测肿瘤转移情况,计量平均肝重指数、肝肺平均表面结节数及肺转移率;肝脏标本及肿瘤组织通过常规HE染色进行病理形态学观察,了解肿瘤生长及转移情况;免疫组化法检测肿瘤血管生成相关蛋白缺氧诱导因子-1α(HIF-1α)、血管内皮生长因子(VEGF)、CD31,肿瘤细胞增值核抗原Ki-67及凋亡相关蛋白caspase-3的表达,CD31标记内皮细胞行肿瘤微血管记数;逆转录聚合酶链反应检测HIF-1αmRNA及VEGF mRNA水平。应用单因素方差分析、χ2检验及Kaplan-Meier法对相应资料分别进行统计学分析。
结果(1)水饲水飞蓟宾200 ppm、l000 ppm、5000 ppm三个剂量组较对照组均能显著增加荷瘤鼠的存活率(92.9%、85.7%、71.9%,对照组为69.2%)、大鼠平均肝重指数(4.56%±0.40%、4.98%±0.50%、9.28%±1.91%,对照组14.25%±3.90%),平均肝/肺表面结节数[(6.13±0.21)/(0.51.±0.21)个、(7.67±0.82)/(0.78.±0.13)个、(11.76±2.15)/(3.11.±0.37)个,对照组(19.32±3.31)/ (4.81.±0.53)个]及肺转移率(15.4%、25.0%、50%对比55.6%)降低,P值均<0.05;微血管密度值显著减少(0.56±0.11、0.62±0.18、2.31±0.64,对照组3.01±0.98),P <0.01;水飞蓟宾各剂量组较对照组肝癌组织中HIF-1α、VEGF、CD31、ki-67蛋白表达及VEGF mRNA水平均有显著下调,而caspase-3蛋白表达则有明显增加,P值均<0.01或0.05, HIF-1αmRNA水平各剂量组均较对照组则无明显差异。
结论水飞蓟宾可显著抑制肝癌的生长及转移,其可能机制如下:(1)、抗肿瘤血管生成,抑制肿瘤生长转移;(2)、通过干预细胞周期进程阻滞肿瘤细胞增殖;(3)、多步骤多途径诱导肿瘤细胞凋亡。
Objective: To investigate the anti-tumor effects of Silybinin (SB) on induced rat model of hepatocellular carcinoma (HCC) and its possible mechanism.
Methods: Diethylnitrosamine (DENA)-induced rat model of HCC was established by using a modifier method. All rats were randomly divided into SB low-dose group (200μg/ml), SB middle-dose group (1000μg/ml), SB high-dose group (5000μg/ml) and control group (equal volume of sterile water), received free drinking water mixed with the drug. During the experimental period, survival situation of rats was dynamically observed. After 8-week drug treatment, all rats were sacrificed and tumor growth and metastasis were examined. Liver and lung specimens were stained by HE to observe the pathomorphological changes as routine. The levels of hypoxia-inducible factor 1 alpha (HIF-1α), vascular endothelial growth factor (VEGF), Ki-67 and caspase-3 proteins and mRNAs were detected by immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR), respectively. Additionally, one-way ANOVA,χ2 test and Kaplan-Meier method were used to statistically analyze the corresponding data.
Results: Compared with the control group (69.2%), SB-treated rats had higher survival rate (92.9%, 85.7% and 71.9%); The mean liver weight index (4.56%±0.40%、4.98%±0.50% and 9.28%±1.91%), the mean liver nodules (6.13±0.21),(7.67±0.82), (11.76±2.15); the mean lung nodules (0.51.±0.21) , (0.78±0.13), (3.11.±0.37) ; the lung metastsis rate ((15.4%、25.0% and 50%), and the intratumoral microvessel density (MVD) (0.56±0.11、0.62±0.18 and 2.31±0.64 ) were lower in rats treated with SB than those in control group, which were 14.25%±3.90%, 19.32±3.31, 4.81.±0.53 and 55.6% respectively (P <0.01 or P <0.05). HIF-1α, VEGF, and Ki67 proteins and VEGF mRNA were more obviously downregulated in SB-treated rats than those in control rats, while Caspase-3 protein was statistically increased. Moreover, the level of HIF-1αmRNA had no difference compared between SB groups and control group.
Conclusions: Silibinin can obviously inhibit tumor growth and metastasis of HCC. The possible associated mechanisms are as follows: (1) Inhibition of tumor growth and metastasis through antiangiogenesis; (2) Inhibition of tumor growth through blockage of cell proliferation; (3) Exerting antitumor effects through induction of cell apoptosis.
引文
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1. Tyagi A, Agarwal C, Harrison G,et al. Silibinin causes cell cycle arrest and apoptosis in human bladder transitional cell carcinoma cells by regulating CDKI-CDK-cyclin cascade, and caspase 3 and PARP cleavages. Carcinogenesis. 2004, 25(9): 1711-1720.
2. Sharma G, Singh RP, Chan DC, et al. Silibinin induces growth inhibition and apoptotic cell death in human lung carcinoma cells. Anticancer Res, 2003, 23(3B): 2649-2655.
3. Agarwal C, Singh RP, Dhanalakshmi S, et al. Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells. Oncogene, 2003, 22(51): 8271-8282.
4. Zi X, Agarwal R. Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. Proc Natl Acad Sci USA, 1999, 96(13): 7490-5.
5. Singh RP, Agarwal R. Prostate cancer prevention by silibinin. Curr Cancer Drug Targets. 2004, 4(1): 1-11.
6. Agarwal R, Katiyar SK, Lundgren DW, et al. Inhibitory effect of silymarin, an anti-hepatotoxic flavonoid, on 12-O-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity and mRNA in SENCAR mice.Carcinogenesis. 1994, 15(6): 1099-1103
7. Zhao J, Lahiri-Chaterijee M, Sharina Y, et al .Inhibitory effect of a flavonoid antioxidant silymarin on henzoyl peroxide-induced humor promotion, oxidative stress and inflammatory responses in SENCAR mouse skin. Carcinogenesis, 2000, 21 (4): 811-816.
8. Lahrri-Chtterjee M, Katiyar SK, Mohan RR, ea al. A flavonoid antioxidant,silymarin, affords exceptionally high protection against tumor promotion in the SENCAR mouse shin tumorigenesis. Cancer Rev, 1999, 59(3): 622-632.
9. Yanida Y, Kohno H, Yoshida K, et al. Dietary silymarin suppresses 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male F344 rats. Carcinogenesis, 2002, 23(5): 787-794.
10. Vinh PQ, Sugie S, Tanaka T, et al. Chemopreventive effects of a flavonoid antioxidant silymarin on N-butyl-n-(4-hydroxybutyl) nitrosanrine-induced urinary bladder Carcinogenesis in male ICR mice. Jpn J Cancer Res, 2002, 93(1): 42-49.
11.吕翔隆,任清梅,支庆江.水飞蓟宾对二乙基亚硝胺诱导的鼠肝致癌作用的保护效应.河北医药, 2008,30(8):1100-1102.
12.农祥,何黎,李谦.紫外线致皮肤肿瘤的研究进展.临床皮肤科杂志,2002,31(11):730-731.
13. Mallikarjuna G, Dhanalakshmi S, Singh RP, et al. Silibinin protects against photocarcinogenesis via modulation of cell cycle regulators, mitogen-activated protein kinases, and akt signaling. Cancer Rev, 2004, 64(17): 6349-6356.
14. Dhanalakshmi S, Mallikarjuna GU, Singh RP, et al. Dual efficacy of silibinin in protecting or enhancing ultraviolet B radiation-caused apoptosis in HaCaT human immortalized keratinocytes. Carcinogenesis, 2004, 25(1): 99-106.
15. Manna SK. Mukhopadhyay A. Van NT, et al. Silymarin suppresses TNF-induced activation of NF-kappaB, c-Jun N-terminal kinase, and apoptosis. J Immunal, 1999, 163(12): 6800-6809.
16. Dhanalakshmi S, Singh RP, Agarwal C, et al. Silibinin inhibits constitutive and TNFalpha-induced activation of NF-kappaB and sensitizes human prostate carcinoma DU145 cells to TNFalpha-indueed apoptosis. Oncogene, 2002, 21(11): 1759-1767
17. Tyagi AK, Singh RP, Agarwal C, et al. Silibinin strongly synergizes human prostate carcinoma DU145 cells to doxorubicin-induced growth Inhibition, G2-Marrest, and apoptosis. Clin Cancer Res, 2002, 8(11): 3512-3519
18. Tyagi A, Agarwal C, Agarwal R. The cancer preventive flavonoid silibinin causes hypophosphorylation of Rb/p107 and Rb2/p130 via modulation of cell cycle regulators in human prostate carcinoma DU145 cells. Cell Cycle, 2002, 1(2): 137-142.
19. Tyagi A, Agarwal C, Agarwal R. Inhibition of retinoblastoma protein(Rb) phosphorylation at serine sites and an increase in Rb-E2F complex formation by silibinin in androgen-dependent human prostate carcinoma LNCaP cells: role in prostate cancer prevention. Mol Cancer Ther, 2002, 1(7): 525-532.
20. Tyagi AK, Agarwal C, Singh RP, et al. Silibinin down-regulates survivin protein and mRNA expression and causes caspases activation and apoptosis in human bladder transitional-cell papilloma RT4 cells. Biochem Biophys Res Commun, 2003, 312(4): 1178-1184.
21. Mohan S, Dhanalakshmi S, Mallikarjuna GU, et al. Silibinin modulates UVB-induced apoptosis via mitochondrial proteins, caspases activation, and mitogen-activated protein kinase signaling in human epidermoid carcinoma A431 cells. Biochem Biophys Res Commun, 2004, Jul 16; 320(1): 183-189.
22. Singh RP,Tyagi AK,Zhao J,et al.Silymarin inhibits growth and causes regression of established skin tumors in SENCAR mice via modulation of mitogen-activated protein kinases and induction of apoptosis.Carcinogenesis,2002, 23(3):499-510.
23. Yoo HG, Jung SN, Hwang YS, et al. Involvement of NF-kappaB and caspases in silibinin-induced apoptosis of endothelial cells. Int J Mol Med, 2004, 13(1): 81-86.
24. Singh RP, Sharma G, Dhanalakshmi S, et al. Suppression of advanced human prostate tumor growth in athymic mice by silibinin feeding is associated with reduced cell proliferation, increased apoptosis, and inhibition of angiogenesis. Cancer Epidemiol Biomarkers Prev. 2003, 12(9): 933-939.
25. Yang SH, Lin JK, Chen WS, et al. Anti-angiogenic effect of silymarin on colon cancer LoVo cell line. J Surg Res, 2003, 113(1): 133-138.
26. Jiang C, Agarwal R, Lu J.Anti-angiogenic potential of a cancer chemopreventive flavonoid antioxidant, silymarin: inhibition of key attributes of vascular endothelial cells and angiogenic cytokine secretion by cancer epithelial cells. Biochem Biophys Res Commun, 2000, 276(1): 371-378.
27. Singh RP, Dhanalakshmi S, Tyagi AK, et al. Dietary feeding of silibinin inhibits advance human prostate carcinoma growth in athymic nude mice and increases plasma insulin-like growth factor-binding protein-3 levels.Cancer Res, 2002, 62(11): 3063-3069.
28. Zi X, Zhang J, Agarwal R, et al. Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells. Cancer Res, 2000, 60(20): 5617-5620.
29. Sharma Y, Agarwal C, Singh AK, et al. Inhibitory effect of silibinin on ligand binding to erbB1 and associated mitogenic signaling, growth, and DNA synthesis in advanced human prostate carcinoma cells. Mol Carcinog, 2001, (4): 224-236.
30. Zi X, Grasso AW, Kung HJ, et al. A flavonoid antioxidant, silymarin, inhibits activation of erbB1 signaling and induces cyclin-dependent kinase inhibitors, G1 arrest, and anticarcinogenic effects in human prostate carcinoma DU145 cells. Cancer Res, 1998, 58(9): 1920-1929.
31. Bhatia N, Agarwal C, Agarwal R. Differential responses of skin cancer chemopreventive agents silibinin,quercetin,and epigallocatechin 3-gallate on mitogenic signaling and cell cycle regulators in human epidermoid carcinoma A431 cells. Nutr Cancer, 2001, 39(2): 292-299.
32. Dhanalakshmi S, Agarwal P, Glode LM, et al. Silibinin sensitizes human prostate carcinoma DU145 cells to cisplatin-and carboplatin-induced growth inhibitionand apoptotic death. Int J Cancer, 2003, 106(5): 699-705.
33. Tyagi AK, Agarwal C, Chan DC, et al. Synergistic anti-cancer effects of silibinin with conventional cytotoxic agents doxorubicin,cisplatin and carboplatin against human breast carcinoma MCF-7 and MDA-MB468 cells. Oncol Rep, 2004, 11(2): 493-499.
34. Zhang S, Morris ME. Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein-mediated transport.J Pharmacol Exp Ther, 2003, 304(3): 1258-1267.
35. Nguyen H, Zhang S. Morris ME.Effect of flavonoids on MRP1-mediated transport in Panc-1 cells. J Pharm Sci, 2003, 92(2): 250-257.
36. Cooray HC, Janvilisri T, van Veen HW, et al. Interaction of the breast cancer resistance protein with plant polyphenols.Biochem Biophys Res Commun, 2004, 317(1): 269-275.
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6. Sharma G, Singh RP, Chan DC, et al. Silibinin induces growth inhibition and apoptotic cell death in human lung carcinoma cells. Anticancer Res, 2003, 23(3B): 2649-2655.
7. Agarwal C, Singh RP, Dhanalakshmi S, et al. Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells. Oncogene, 2003, 22(51): 8271-8282.
8. Zi X, Agarwal R. Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. Proc Natl Acad Sci USA, 1999, 96(13): 7490-7495.
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14. Lahrri-Chtterjee M, Katiyar SK, Mohan RR, ea al. A flavonoid antioxidant, silymarin, affords exceptionally high protection against tumor promotion in the SENCAR mouse shin tumorigenesis. Cancer Rev, 1999, 59(3); 622-632.
15. Yanida Y, Kohno H, Yoshida K, et al. Dietary silymarin suppresses 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male F344 rats. Carcinogenesis, 2002, 23(5): 787-794.
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38. Singh RP, Sharma G, Dhanalakshmi S, et al. Suppression of advanced human prostate tumor growth in athymic mice by silibinin feeding is associated with reduced cell proliferation, increased apoptosis, and inhibition of angiogenesis. Cancer Epidemiol Biomarkers Prev, 2003, 12(9): 933-939.
39. Yang SH, Lin JK, Chen WS, et al. Anti-angiogenic effect of silymarin on colon cancer LoVo cell line. J Surg Res, 2003, 113(1): 133-138.
40. Jiang C, Agarwal R, Lu J.Anti-angiogenic potential of a cancer chemopreventive flavonoid antioxidant, silymarin: inhibition of key attributes of vascular endothelial cells and angiogenic cytokine secretion by cancer epithelial cells. Biochem Biophys Res Commun, 2000, 276(1):371-378.
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46. Mohan S, Dhanalakshmi S, Mallikarjuna GU, et al. Silibinin modulates UVB-induced apoptosis via mitochondrial proteins, caspases activation, and mitogen-activated protein kinase signaling in human epidermoid carcinoma A431 cells. Biochem Biophys Res Commun, 2004, 320(1): 183-189.
47. Singh RP, Tyagi AK, Zhao J, et al. Silymarin inhibits growth and causes regression of established skin tumors in SENCAR mice via modulation of mitogen-activated protein kinases and induction of apoptosis. Carcinogenesis, 2002, 23(3): 499-510.
1. Tyagi A, Agarwal C, Harrison G,et al. Silibinin causes cell cycle arrest and apoptosis in human bladder transitional cell carcinoma cells by regulating CDKI-CDK-cyclin cascade, and caspase 3 and PARP cleavages. Carcinogenesis. 2004, 25(9): 1711-1720.
2. Sharma G, Singh RP, Chan DC, et al. Silibinin induces growth inhibition and apoptotic cell death in human lung carcinoma cells. Anticancer Res, 2003, 23(3B): 2649-2655.
3. Agarwal C, Singh RP, Dhanalakshmi S, et al. Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells. Oncogene, 2003, 22(51): 8271-8282.
4. Zi X, Agarwal R. Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: implications for prostate cancer intervention. Proc Natl Acad Sci USA, 1999, 96(13): 7490-5.
5. Singh RP, Agarwal R. Prostate cancer prevention by silibinin. Curr Cancer Drug Targets. 2004, 4(1): 1-11.
6. Agarwal R, Katiyar SK, Lundgren DW, et al. Inhibitory effect of silymarin, an anti-hepatotoxic flavonoid, on 12-O-tetradecanoylphorbol-13-acetate-induced epidermal ornithine decarboxylase activity and mRNA in SENCAR mice.Carcinogenesis. 1994, 15(6): 1099-1103
7. Zhao J, Lahiri-Chaterijee M, Sharina Y, et al .Inhibitory effect of a flavonoid antioxidant silymarin on henzoyl peroxide-induced humor promotion, oxidative stress and inflammatory responses in SENCAR mouse skin. Carcinogenesis, 2000, 21 (4): 811-816.
8. Lahrri-Chtterjee M, Katiyar SK, Mohan RR, ea al. A flavonoid antioxidant,silymarin, affords exceptionally high protection against tumor promotion in the SENCAR mouse shin tumorigenesis. Cancer Rev, 1999, 59(3): 622-632.
9. Yanida Y, Kohno H, Yoshida K, et al. Dietary silymarin suppresses 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male F344 rats. Carcinogenesis, 2002, 23(5): 787-794.
10. Vinh PQ, Sugie S, Tanaka T, et al. Chemopreventive effects of a flavonoid antioxidant silymarin on N-butyl-n-(4-hydroxybutyl) nitrosanrine-induced urinary bladder Carcinogenesis in male ICR mice. Jpn J Cancer Res, 2002, 93(1): 42-49.
11.吕翔隆,任清梅,支庆江.水飞蓟宾对二乙基亚硝胺诱导的鼠肝致癌作用的保护效应.河北医药, 2008,30(8):1100-1102.
12.农祥,何黎,李谦.紫外线致皮肤肿瘤的研究进展.临床皮肤科杂志,2002,31(11):730-731.
13. Mallikarjuna G, Dhanalakshmi S, Singh RP, et al. Silibinin protects against photocarcinogenesis via modulation of cell cycle regulators, mitogen-activated protein kinases, and akt signaling. Cancer Rev, 2004, 64(17): 6349-6356.
14. Dhanalakshmi S, Mallikarjuna GU, Singh RP, et al. Dual efficacy of silibinin in protecting or enhancing ultraviolet B radiation-caused apoptosis in HaCaT human immortalized keratinocytes. Carcinogenesis, 2004, 25(1): 99-106.
15. Manna SK. Mukhopadhyay A. Van NT, et al. Silymarin suppresses TNF-induced activation of NF-kappaB, c-Jun N-terminal kinase, and apoptosis. J Immunal, 1999, 163(12): 6800-6809.
16. Dhanalakshmi S, Singh RP, Agarwal C, et al. Silibinin inhibits constitutive and TNFalpha-induced activation of NF-kappaB and sensitizes human prostate carcinoma DU145 cells to TNFalpha-indueed apoptosis. Oncogene, 2002, 21(11): 1759-1767
17. Tyagi AK, Singh RP, Agarwal C, et al. Silibinin strongly synergizes human prostate carcinoma DU145 cells to doxorubicin-induced growth Inhibition, G2-Marrest, and apoptosis. Clin Cancer Res, 2002, 8(11): 3512-3519
18. Tyagi A, Agarwal C, Agarwal R. The cancer preventive flavonoid silibinin causes hypophosphorylation of Rb/p107 and Rb2/p130 via modulation of cell cycle regulators in human prostate carcinoma DU145 cells. Cell Cycle, 2002, 1(2): 137-142.
19. Tyagi A, Agarwal C, Agarwal R. Inhibition of retinoblastoma protein(Rb) phosphorylation at serine sites and an increase in Rb-E2F complex formation by silibinin in androgen-dependent human prostate carcinoma LNCaP cells: role in prostate cancer prevention. Mol Cancer Ther, 2002, 1(7): 525-532.
20. Tyagi AK, Agarwal C, Singh RP, et al. Silibinin down-regulates survivin protein and mRNA expression and causes caspases activation and apoptosis in human bladder transitional-cell papilloma RT4 cells. Biochem Biophys Res Commun, 2003, 312(4): 1178-1184.
21. Mohan S, Dhanalakshmi S, Mallikarjuna GU, et al. Silibinin modulates UVB-induced apoptosis via mitochondrial proteins, caspases activation, and mitogen-activated protein kinase signaling in human epidermoid carcinoma A431 cells. Biochem Biophys Res Commun, 2004, Jul 16; 320(1): 183-189.
22. Singh RP,Tyagi AK,Zhao J,et al.Silymarin inhibits growth and causes regression of established skin tumors in SENCAR mice via modulation of mitogen-activated protein kinases and induction of apoptosis.Carcinogenesis,2002, 23(3):499-510.
23. Yoo HG, Jung SN, Hwang YS, et al. Involvement of NF-kappaB and caspases in silibinin-induced apoptosis of endothelial cells. Int J Mol Med, 2004, 13(1): 81-86.
24. Singh RP, Sharma G, Dhanalakshmi S, et al. Suppression of advanced human prostate tumor growth in athymic mice by silibinin feeding is associated with reduced cell proliferation, increased apoptosis, and inhibition of angiogenesis. Cancer Epidemiol Biomarkers Prev. 2003, 12(9): 933-939.
25. Yang SH, Lin JK, Chen WS, et al. Anti-angiogenic effect of silymarin on colon cancer LoVo cell line. J Surg Res, 2003, 113(1): 133-138.
26. Jiang C, Agarwal R, Lu J.Anti-angiogenic potential of a cancer chemopreventive flavonoid antioxidant, silymarin: inhibition of key attributes of vascular endothelial cells and angiogenic cytokine secretion by cancer epithelial cells. Biochem Biophys Res Commun, 2000, 276(1): 371-378.
27. Singh RP, Dhanalakshmi S, Tyagi AK, et al. Dietary feeding of silibinin inhibits advance human prostate carcinoma growth in athymic nude mice and increases plasma insulin-like growth factor-binding protein-3 levels.Cancer Res, 2002, 62(11): 3063-3069.
28. Zi X, Zhang J, Agarwal R, et al. Silibinin up-regulates insulin-like growth factor-binding protein 3 expression and inhibits proliferation of androgen-independent prostate cancer cells. Cancer Res, 2000, 60(20): 5617-5620.
29. Sharma Y, Agarwal C, Singh AK, et al. Inhibitory effect of silibinin on ligand binding to erbB1 and associated mitogenic signaling, growth, and DNA synthesis in advanced human prostate carcinoma cells. Mol Carcinog, 2001, (4): 224-236.
30. Zi X, Grasso AW, Kung HJ, et al. A flavonoid antioxidant, silymarin, inhibits activation of erbB1 signaling and induces cyclin-dependent kinase inhibitors, G1 arrest, and anticarcinogenic effects in human prostate carcinoma DU145 cells. Cancer Res, 1998, 58(9): 1920-1929.
31. Bhatia N, Agarwal C, Agarwal R. Differential responses of skin cancer chemopreventive agents silibinin,quercetin,and epigallocatechin 3-gallate on mitogenic signaling and cell cycle regulators in human epidermoid carcinoma A431 cells. Nutr Cancer, 2001, 39(2): 292-299.
32. Dhanalakshmi S, Agarwal P, Glode LM, et al. Silibinin sensitizes human prostate carcinoma DU145 cells to cisplatin-and carboplatin-induced growth inhibitionand apoptotic death. Int J Cancer, 2003, 106(5): 699-705.
33. Tyagi AK, Agarwal C, Chan DC, et al. Synergistic anti-cancer effects of silibinin with conventional cytotoxic agents doxorubicin,cisplatin and carboplatin against human breast carcinoma MCF-7 and MDA-MB468 cells. Oncol Rep, 2004, 11(2): 493-499.
34. Zhang S, Morris ME. Effects of the flavonoids biochanin A, morin, phloretin, and silymarin on P-glycoprotein-mediated transport.J Pharmacol Exp Ther, 2003, 304(3): 1258-1267.
35. Nguyen H, Zhang S. Morris ME.Effect of flavonoids on MRP1-mediated transport in Panc-1 cells. J Pharm Sci, 2003, 92(2): 250-257.
36. Cooray HC, Janvilisri T, van Veen HW, et al. Interaction of the breast cancer resistance protein with plant polyphenols.Biochem Biophys Res Commun, 2004, 317(1): 269-275.