黄连素对乳腺癌细胞生长、转移和放射敏感性的影响
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摘要
目的研究黄连素对乳腺癌细胞生长、转移和放射敏感性的影响。
方法MTT法检测细胞的生长和增殖;划痕愈合法观察细胞迁徙能力;流式细胞术测定细胞周期改变和细胞凋亡;磷脂酰丝氨酸外翻分析法检测细胞凋亡;Western-blot法测定蛋白表达水平;细胞克隆形成法观察黄连素与辐射对放射敏感性的联合作用。
结果黄连素明显抑制人乳腺癌MCF-7和MDA-MB-231细胞的生长,并显现剂量-效应和处理时间-效应关系,而且MCF-7和MDA-MB-231细胞系对黄连素表现出同样的敏感性。黄连素可以诱导剂量依赖性的G0/G1期细胞阻滞和细胞凋亡。黄连素明显降低了细胞周期调节相关蛋白Cyclin D1和抗细胞凋亡蛋白Bcl-2的表达水平,而增加了凋亡蛋白Bax和caspase-3的表达水平,同时细胞周期调节蛋白Cyclin B1的表达水平降低,但不引起G2/M期阻滞。黄连素在低毒性剂量可以明显降低乳腺癌细胞迁徙能力。采用单靶多击模型拟合曲线发现,与没有用黄连素处理的对照细胞相比,黄连素处理后的MCF-7和MDA-MB-231细胞都出现无肩的生存曲线。
结论黄连素通过诱导细胞凋亡和细胞周期阻滞抑制乳腺癌细胞生长。而且在低毒性剂量下黄连素可以明显降低乳腺癌细胞的迁徙和转移能力,并增加乳腺癌细胞对放射治疗的敏感性。这些研究结果表明黄连素可以作为乳腺癌新治疗药物,也为黄连素的深入研究提供了实验基础和理论依据。
Objective : To study the imapcts of berberine on growth, invasion and radiosensitivity in human breast cancer cells.
Methods:(1) MTT assay was used to evaluate cell growth; (2) In vitro scratch migration assay was used to determine cell migration; (3) Annexin V assay was used to detect cell apoptosis; (4) Distribution of cell cycle and apoptosis were analyzed by flow cytometry assay; (5) Colony formation assay was emplyed to detect the influence of berberine on cell radiosensitivity; (6) Western blot assay was employd to measure protein expression.
Results:Berberine inhibited cell growth and migration in two human breast cancer cell lines, MCF-7 and MDA-MB-231, in a dose- and time-denependent manner. Furthermore, berberine resulted in a G0/G1 cell cycle arrest and triggered apoptosis. Berberine caused a dose-dependent increase of bax and caspase-3 protein expression, while the expression of cyclin D1 cyclin B1 and Bcl-2 protein was suppressed. Additionally, a disapperance of shoulder of cell survival curves after irradiation was observed in both MCF-7 and MDA-MB-231 cell lines in the presence of berberine compared with the absence of berberine.
Conclusion: The present findings have demonstrated that berberine inhibits growth and invasion of breast cancer cells via apoptosis induction and cycle cycle arrest. Moreover, berberine at lower doses repressed cell migration and increases cell sensitivity toχ-ray irradiation. These results provide evidence for further investigation of berberine as a new anti-cancer agent and radiosensitizer in therapy of breast cancer.
方法MTT法检测细胞的生长和增殖;划痕愈合法观察细胞迁徙能力;流式细胞术测定细胞周期改变和细胞凋亡;磷脂酰丝氨酸外翻分析法检测细胞凋亡;Western-blot法测定蛋白表达水平;细胞克隆形成法观察黄连素与辐射对放射敏感性的联合作用。
结果黄连素明显抑制人乳腺癌MCF-7和MDA-MB-231细胞的生长,并显现剂量-效应和处理时间-效应关系,而且MCF-7和MDA-MB-231细胞系对黄连素表现出同样的敏感性。黄连素可以诱导剂量依赖性的G0/G1期细胞阻滞和细胞凋亡。黄连素明显降低了细胞周期调节相关蛋白Cyclin D1和抗细胞凋亡蛋白Bcl-2的表达水平,而增加了凋亡蛋白Bax和caspase-3的表达水平,同时细胞周期调节蛋白Cyclin B1的表达水平降低,但不引起G2/M期阻滞。黄连素在低毒性剂量可以明显降低乳腺癌细胞迁徙能力。采用单靶多击模型拟合曲线发现,与没有用黄连素处理的对照细胞相比,黄连素处理后的MCF-7和MDA-MB-231细胞都出现无肩的生存曲线。
结论黄连素通过诱导细胞凋亡和细胞周期阻滞抑制乳腺癌细胞生长。而且在低毒性剂量下黄连素可以明显降低乳腺癌细胞的迁徙和转移能力,并增加乳腺癌细胞对放射治疗的敏感性。这些研究结果表明黄连素可以作为乳腺癌新治疗药物,也为黄连素的深入研究提供了实验基础和理论依据。
Objective : To study the imapcts of berberine on growth, invasion and radiosensitivity in human breast cancer cells.
Methods:(1) MTT assay was used to evaluate cell growth; (2) In vitro scratch migration assay was used to determine cell migration; (3) Annexin V assay was used to detect cell apoptosis; (4) Distribution of cell cycle and apoptosis were analyzed by flow cytometry assay; (5) Colony formation assay was emplyed to detect the influence of berberine on cell radiosensitivity; (6) Western blot assay was employd to measure protein expression.
Results:Berberine inhibited cell growth and migration in two human breast cancer cell lines, MCF-7 and MDA-MB-231, in a dose- and time-denependent manner. Furthermore, berberine resulted in a G0/G1 cell cycle arrest and triggered apoptosis. Berberine caused a dose-dependent increase of bax and caspase-3 protein expression, while the expression of cyclin D1 cyclin B1 and Bcl-2 protein was suppressed. Additionally, a disapperance of shoulder of cell survival curves after irradiation was observed in both MCF-7 and MDA-MB-231 cell lines in the presence of berberine compared with the absence of berberine.
Conclusion: The present findings have demonstrated that berberine inhibits growth and invasion of breast cancer cells via apoptosis induction and cycle cycle arrest. Moreover, berberine at lower doses repressed cell migration and increases cell sensitivity toχ-ray irradiation. These results provide evidence for further investigation of berberine as a new anti-cancer agent and radiosensitizer in therapy of breast cancer.
引文
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6. Yu HH, Kim KJ, Cha JD, et al. Antimicrobial activity of berberine alone and in combination with ampicillin or oxacillin against methicillin resistant Staphylococcus aureus. J Med Food, 2005, 8(4): 454-461.
7. Park KD, Lee JH, Kim SH,et al. Synthesis of 13 (substituted benzyl) berberine and berberrubine derivatives as antifungal agents. Bioorg Med Chem Lett, 2006, 16(15): 3913-3916.
8. Wu LT, Tsou MF, Ho CC, et al. Berberine inhibits arylamine N-acetyltransferase activity and gene expression in Salmonella typhi. Curr Microbiol, 2005, 51(4): 255-261.
9. Hayashi K, Minoda K, Nagaoka Y, et al. Antiviral activity of berberine and related compounds against human cytomegalovirus. Bioorg Med Chem Lett, 2007, 17(6): 1562-1564.
10. Choi BH, Ahn IS, Kim YH, et al. Berberine reduces the expression of adipogenicenzymes and inflammatory molecules of 3T3 L1 adipocyte. Exp Mol Med, 2006, 38(6): 599-605.
11. Li F, Wang HD, Lu DX, et al. Neutral sulfate berberine modulates cytokine secretion and increases survival in endotoxemic mice. Acta Pharmacol Sin, 2006, 27(9): 1199-1205.
12. Yokozawa T, Ishida A, Kashiwada Y, et al. Coptidis Rhizoma: protective effects against peroxynitrite induced oxidative damage and elucidation of its active components. J Pharm Pharmacol, 2004, 56(4): 547-556.
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23. Peng PL, Kuo WH, Tseng HC, Chou FP. Synergistic tumor-killing effect of radiation and berberine combined treatment in lung cancer: the contribution of autophagic cell death. Int J Radiat Oncol Biol Phys, 2008, 70(2): 529-42.
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27. Kim WS, Lee YS, Cha SH, et al. Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity. Am J Physiol Endocrinol Metab 2009, 296(4): E812-9.
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1. Kim S, Choi JH, Kim JB, et al. Berberine suppresses TNF-alpha-induced MMP-9 and cell invasion through inhibition of AP-1 activity in MDA-MB-231 human breast cancer cells. Molecules, 2008, 13(12): 2975-2985.
2.杨菁,林菁.黄连素临床应用的研究.医学综述,2008,14(2):297-299.
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4. Tang J, Feng Y, Tsao S, et al. Berberine and Coptidis rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigations. J Ethnopharmaco, 2009, 29, 126(1): 5-17.
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1.凌大军.试述黄连素的药理作用.亚太传统医药,2008,4(9):138-139.
2.杨菁,林菁.黄连素临床应用的研究.医学综述,2008,14(2):297-299.
3. Sun Y, Xun K, Wang Y, et al. A systematic review of the anticancer properties of berberine, a natural product from Chinese herbs. Anticancer Drugs, 2009, 20(9): 757-769.
4. Tang J, Feng Y, Tsao S, et al. Berberine and Coptidis rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigations. J Ethnopharmaco, 2009, 29, 126(1): 5-17.
5.王福军,石翔,周晓英,等.黄连素在心血管疾病中的应用现状.实用心电学杂志,2009,18(1):1777-1778.
6.施春晓.黄连素联合格列齐特治疗2型糖尿病的临床疗效观察.临床与实验医学杂志,2009,8(6):92-93.
7.闻菊生.黄连素合罗通定治疗频发性室性早搏的疗效观察.现代中西医结合杂志,2000,9(2):132-133.
8. Hoshi A, Ikekawa T, et al. Antitumor activity of berberine derivatives. Gann, 1976, 67(4): 321.
9. Sun Y, Xun K, Wang Y, et al. A systematic review of the anticancer properties of berberine, a natural product from Chinese herbs. Anticancer Drugs, 2009, 20(9): 757-769.
10. Tang J, Feng Y, Tsao S, et al. Berberine and Coptidis rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigations. J Ethnopharmaco, 2009, 126(1): 5-17.
11.马学强,朱雄文,梁斌,刘曾旭,刘德明,刘翰林.黄连素联合胞嘧啶脱氨酶自杀基因对直肠癌细胞凋亡的影响.实用医学杂志,2009,(05):689-692.
12. Peng PL, Kuo WH, Tseng HC, Chou FP. Synergistic tumor-killing effect of radiation and berberine combined treatment in lung cancer: the contribution of autophagic cell death. Int J Radiat Oncol Biol Phys. 2008. 70(2): 529-42.
13. Lin JP, Yang JS, Wu CC, et al. Berberine induced down-regulation of matrix metalloproteinase-1, -2 and -9 in human gastric cancer cells (SNU-5) in vitro. In Vivo. 2008. 22(2): 223-30.
14. Lin JP, Yang JS, Chang NW, et al. GADD153 mediates berberine-induced apoptosis in human cervical cancer Ca ski cells. Anticancer Res, 2007, 27(5A): 3379-3386.
15. Muralimanoharan SB, Kunnumakkara AB, Shylesh B, et al. Butanol fraction containing berberine or related compound from nexrutine inhibits NFkappaB signaling and induces apoptosis in prostate cancer cells. Prostate, 2009, 69(5): 494-504.
16. Kim WS, Lee YS, Cha SH, et al. Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity. Am J Physiol Endocrinol Metab, 2009, 296(4): E812-9.
17. Khan M, Giessrigl B, Vonach C, et al. Berberine and a Berberis lycium extract inactivate Cdc25A and induce alpha-tubulin acetylation that correlate with HL-60 cell cycle inhibition and apoptosis. Mutat Res, 2010, 683(1-2): 123-130.
18. Eom KS, Hong JM, Youn MJ, et al. Berberine induces G1 arrest and apoptosis in human glioblastoma T98G cells through mitochondrial/caspases pathway. Biol Pharm Bull, 2008, 31(4): 558-62.
19. Mantena SK, Sharma SD, Katiyar SK. Berberine inhibits growth, induces G1 arrest and apoptosis in human epidermoid carcinoma A431 cells by regulating Cdki-Cdk-cyclin cascade, disruption of mitochondrial membrane potential and cleavage of caspase 3 and PARP. Carcinogenesis, 2006, 27(10): 2018-27.
20.张卫东,吴定国,王金松,赵勇.黄连素对人肝癌Hep G2细胞周期及凋亡的影响.武汉大学报(医学版),2008,29(6):766-786.
21. Lin JG, Chung JG, et al.Effects of berberine on aryl-amine N-acetyltransferase activity in human colon tumor cells. Am J Chin Med, 1999, 27(2): 265-275.
22. Lin CC,Kao ST, et al. Berberine decreased N-acetylation of 2-aminofluorene through inhibition of N-acetyltransferase gene expression in human leukemia HL-60 cells.Anticancer Res, 2005, 25(6b): 4149-55.
23. Fukuda K, Hibiya Y, et al. Inhibition of activatior protein-1 activity by berberine in human hepatoma cells. Planta Med, 1999, 65(4): 381.
24. Kim S,Choi JH, et al. Berberine supperesses TNF-alpha-induced MMP-9 and cell invasion through inhibition of AP-1 activity in MDA-MB-231 human breast canner cells.Molecules, 2008, 13(12): 2975-85
25. Chen KT, Hao DM et al. Effect of berberine alone or in combination with argon ion laser treatment on 9L ratglioma celline. Chin Med J(Engl), 1994, 107(11): 808.
26. Muralimanoharan SB, Kunnumakkara AB, et al. Butanol fraction containing berberine or related compound from nexrutine inhibits NfkappaB signaling and induces apoptosis in prostate cancer cells. Prostate, 2009, 69(5): 494-504.
27. Lizuka N, Miyamoto K, et al. Anticachectic effects of Coptidis Rhizoma,an antti-inflammatory herb, on esophageal cancer cells that produce interleukin-6. Cancer Lett, 2000, 158(1): 35.
2.董志伟,谷铣之.临床肿瘤学.北京:人民卫生出版社,2002:327.
3.殷蔚伯,余子豪.肿瘤放射治疗学.中国协和医科大学出版社,2008:1171.
4. Jiang CB, Liu XF, He YX. Effect of DNA-PKcs antisense oligodeoxynucleotides on radiosensitivity of nasopharyngeal carcinoma cell lines with different p53 function statuses. Ai Zheng, 2008, 27(2): 139-143.
5. D'omina EA, Riabchenko NM, Baryliak IR. Effect of reparation processes on formation of human individual radiosensitivity at the chromosome level. Tsitol Genet, 2008, 42(2): 42-45.
6. Yu HH, Kim KJ, Cha JD, et al. Antimicrobial activity of berberine alone and in combination with ampicillin or oxacillin against methicillin resistant Staphylococcus aureus. J Med Food, 2005, 8(4): 454-461.
7. Park KD, Lee JH, Kim SH,et al. Synthesis of 13 (substituted benzyl) berberine and berberrubine derivatives as antifungal agents. Bioorg Med Chem Lett, 2006, 16(15): 3913-3916.
8. Wu LT, Tsou MF, Ho CC, et al. Berberine inhibits arylamine N-acetyltransferase activity and gene expression in Salmonella typhi. Curr Microbiol, 2005, 51(4): 255-261.
9. Hayashi K, Minoda K, Nagaoka Y, et al. Antiviral activity of berberine and related compounds against human cytomegalovirus. Bioorg Med Chem Lett, 2007, 17(6): 1562-1564.
10. Choi BH, Ahn IS, Kim YH, et al. Berberine reduces the expression of adipogenicenzymes and inflammatory molecules of 3T3 L1 adipocyte. Exp Mol Med, 2006, 38(6): 599-605.
11. Li F, Wang HD, Lu DX, et al. Neutral sulfate berberine modulates cytokine secretion and increases survival in endotoxemic mice. Acta Pharmacol Sin, 2006, 27(9): 1199-1205.
12. Yokozawa T, Ishida A, Kashiwada Y, et al. Coptidis Rhizoma: protective effects against peroxynitrite induced oxidative damage and elucidation of its active components. J Pharm Pharmacol, 2004, 56(4): 547-556.
13. Bustanji Y, Taha MO, Yousef AM, et al. Berberine potently inhibits protein tyrosine phosphatase 1B: investigation by docking simulation and experimental validation. J Enzyme Inhib Med Chem, 2006, 21(2): 163-171.
14. Craig WJ. Health-promoting properties of common herbs. Am J Clin Nutr. 1999, 70(3 Suppl): 491S-499S.
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1.凌大军.试述黄连素的药理作用.亚太传统医药,2008,4(9):138-139.
2.杨菁,林菁.黄连素临床应用的研究.医学综述,2008,14(2):297-299.
3. Sun Y, Xun K, Wang Y, et al. A systematic review of the anticancer properties of berberine, a natural product from Chinese herbs. Anticancer Drugs, 2009, 20(9): 757-769.
4. Tang J, Feng Y, Tsao S, et al. Berberine and Coptidis rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigations. J Ethnopharmaco, 2009, 29, 126(1): 5-17.
5.王福军,石翔,周晓英,等.黄连素在心血管疾病中的应用现状.实用心电学杂志,2009,18(1):1777-1778.
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9. Sun Y, Xun K, Wang Y, et al. A systematic review of the anticancer properties of berberine, a natural product from Chinese herbs. Anticancer Drugs, 2009, 20(9): 757-769.
10. Tang J, Feng Y, Tsao S, et al. Berberine and Coptidis rhizoma as novel antineoplastic agents: a review of traditional use and biomedical investigations. J Ethnopharmaco, 2009, 126(1): 5-17.
11.马学强,朱雄文,梁斌,刘曾旭,刘德明,刘翰林.黄连素联合胞嘧啶脱氨酶自杀基因对直肠癌细胞凋亡的影响.实用医学杂志,2009,(05):689-692.
12. Peng PL, Kuo WH, Tseng HC, Chou FP. Synergistic tumor-killing effect of radiation and berberine combined treatment in lung cancer: the contribution of autophagic cell death. Int J Radiat Oncol Biol Phys. 2008. 70(2): 529-42.
13. Lin JP, Yang JS, Wu CC, et al. Berberine induced down-regulation of matrix metalloproteinase-1, -2 and -9 in human gastric cancer cells (SNU-5) in vitro. In Vivo. 2008. 22(2): 223-30.
14. Lin JP, Yang JS, Chang NW, et al. GADD153 mediates berberine-induced apoptosis in human cervical cancer Ca ski cells. Anticancer Res, 2007, 27(5A): 3379-3386.
15. Muralimanoharan SB, Kunnumakkara AB, Shylesh B, et al. Butanol fraction containing berberine or related compound from nexrutine inhibits NFkappaB signaling and induces apoptosis in prostate cancer cells. Prostate, 2009, 69(5): 494-504.
16. Kim WS, Lee YS, Cha SH, et al. Berberine improves lipid dysregulation in obesity by controlling central and peripheral AMPK activity. Am J Physiol Endocrinol Metab, 2009, 296(4): E812-9.
17. Khan M, Giessrigl B, Vonach C, et al. Berberine and a Berberis lycium extract inactivate Cdc25A and induce alpha-tubulin acetylation that correlate with HL-60 cell cycle inhibition and apoptosis. Mutat Res, 2010, 683(1-2): 123-130.
18. Eom KS, Hong JM, Youn MJ, et al. Berberine induces G1 arrest and apoptosis in human glioblastoma T98G cells through mitochondrial/caspases pathway. Biol Pharm Bull, 2008, 31(4): 558-62.
19. Mantena SK, Sharma SD, Katiyar SK. Berberine inhibits growth, induces G1 arrest and apoptosis in human epidermoid carcinoma A431 cells by regulating Cdki-Cdk-cyclin cascade, disruption of mitochondrial membrane potential and cleavage of caspase 3 and PARP. Carcinogenesis, 2006, 27(10): 2018-27.
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24. Kim S,Choi JH, et al. Berberine supperesses TNF-alpha-induced MMP-9 and cell invasion through inhibition of AP-1 activity in MDA-MB-231 human breast canner cells.Molecules, 2008, 13(12): 2975-85
25. Chen KT, Hao DM et al. Effect of berberine alone or in combination with argon ion laser treatment on 9L ratglioma celline. Chin Med J(Engl), 1994, 107(11): 808.
26. Muralimanoharan SB, Kunnumakkara AB, et al. Butanol fraction containing berberine or related compound from nexrutine inhibits NfkappaB signaling and induces apoptosis in prostate cancer cells. Prostate, 2009, 69(5): 494-504.
27. Lizuka N, Miyamoto K, et al. Anticachectic effects of Coptidis Rhizoma,an antti-inflammatory herb, on esophageal cancer cells that produce interleukin-6. Cancer Lett, 2000, 158(1): 35.
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