苦参碱对雄激素依赖性前列腺癌细胞株LNCaP的抑制作用
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摘要
目的：探讨苦参碱(matrine)对雄激素依赖性前列腺癌细胞株(LNCaP)的凋亡及雄激素受体(androgen receptor，AR)、前列腺特异抗原(prostate specific antigen，PSA)表达的影响。
方法：分别用0．5g/L、1．0g/L、1．5g/L、2．0g/L、3．0g/L浓度的苦参碱作用LNCaP细胞12、24、36 h后MTT法检测细胞生长活性；台盼蓝拒染法测定细胞生长曲线；24 h后流式细胞仪测定细胞周期时相变化及检测细胞凋亡；24 h后Western印迹法检测细胞内Bcl-2和Bax的表达；24 h后Western印迹法检测细胞内AR的表达；12、24、36 h后化学发光法检测LNCaP细胞培养液中PSA的变化。
结果：苦参碱能抑制LNCaP细胞的生长，呈剂量与时间依赖性(P＜0．01)；苦参碱诱导LNCaP细胞出现剂量依赖性G_2／M期阻滞(P＜0．01)；苦参碱诱导LNCaP细胞凋亡，各浓度组凋亡细胞比例均显著高于对照组，差异有显著性意义(P＜0．05)；LNCaP细胞内Bcl-2含量呈浓度依赖性下降，Bax含量呈浓度依赖性升高(P＜0．01)；细胞内AR的表达随苦参碱剂量依赖性减少(P＜0．01)；LNCaP细胞培养液中PSA的表达显著下降(P＜0．05)。
结论：苦参碱对LNCaP细胞生长抑制作用一方面是通过阻滞细胞周期，调控凋亡基因Bcl-2／Bax蛋白的表达来诱导细胞凋亡而实现；另一方面通过抑制前列腺癌细胞中AR表达，延缓前列腺癌发生、发展而实现。并对PSA表达也有抑制作用。
Purposc:To study the effect of matrine on the apoptosis and expression of AR and PSA inprostate cancer cells LNCaP.
Methods:After being treated with 0.5～3.0g/L matrine for 12～36 h,the growth activities ofcancer cells were studied by MTT colorimetry and trypan blue stain assay.Cell cycle phases andapoptosis were inspected by flowcy-tometery(FCM).The levels of Bcl-2 and Bax were tested byWestern Botting.The Levels of AR were tested by Western Botting.The expression of prostatespecific antigen(PSA) was measured by AXSYM system-chemical luciferase methods.
Results:Matrine could effectively inhibit the in vitro growth of androgen dependentprostate cancer cell line LNCaP in time-and-dose-dependent manners(P＜0.01).Cell cycleswere arrested at G_2/M phase(P＜0.01).Partial cancer cells presented apoptosis(P＜0.05).Matrine could decrease in the levels of Bcl-2 and increase in the levels of Bax in cell lineLNCaP in a dose-dependent manner(P＜0.01).Matrine could decrease in the levels of ARin cell line LNCaP in a dose-dependent manner(P＜0.01).Matrine inhibited the expressionof PSA on prostate cancer cells(P＜0.05).
Conclusions:Matrine could suppress the growth of LNCaP,and promotes their apoptosis.Matrine also inhibited the expression of AR and PSA on prostate cancer cells.
Key words:prostate cancer;matrine;LNCaP cells;androgen receptor;prostate specific antigen
方法：分别用0．5g/L、1．0g/L、1．5g/L、2．0g/L、3．0g/L浓度的苦参碱作用LNCaP细胞12、24、36 h后MTT法检测细胞生长活性；台盼蓝拒染法测定细胞生长曲线；24 h后流式细胞仪测定细胞周期时相变化及检测细胞凋亡；24 h后Western印迹法检测细胞内Bcl-2和Bax的表达；24 h后Western印迹法检测细胞内AR的表达；12、24、36 h后化学发光法检测LNCaP细胞培养液中PSA的变化。
结果：苦参碱能抑制LNCaP细胞的生长，呈剂量与时间依赖性(P＜0．01)；苦参碱诱导LNCaP细胞出现剂量依赖性G_2／M期阻滞(P＜0．01)；苦参碱诱导LNCaP细胞凋亡，各浓度组凋亡细胞比例均显著高于对照组，差异有显著性意义(P＜0．05)；LNCaP细胞内Bcl-2含量呈浓度依赖性下降，Bax含量呈浓度依赖性升高(P＜0．01)；细胞内AR的表达随苦参碱剂量依赖性减少(P＜0．01)；LNCaP细胞培养液中PSA的表达显著下降(P＜0．05)。
结论：苦参碱对LNCaP细胞生长抑制作用一方面是通过阻滞细胞周期，调控凋亡基因Bcl-2／Bax蛋白的表达来诱导细胞凋亡而实现；另一方面通过抑制前列腺癌细胞中AR表达，延缓前列腺癌发生、发展而实现。并对PSA表达也有抑制作用。
Purposc:To study the effect of matrine on the apoptosis and expression of AR and PSA inprostate cancer cells LNCaP.
Methods:After being treated with 0.5～3.0g/L matrine for 12～36 h,the growth activities ofcancer cells were studied by MTT colorimetry and trypan blue stain assay.Cell cycle phases andapoptosis were inspected by flowcy-tometery(FCM).The levels of Bcl-2 and Bax were tested byWestern Botting.The Levels of AR were tested by Western Botting.The expression of prostatespecific antigen(PSA) was measured by AXSYM system-chemical luciferase methods.
Results:Matrine could effectively inhibit the in vitro growth of androgen dependentprostate cancer cell line LNCaP in time-and-dose-dependent manners(P＜0.01).Cell cycleswere arrested at G_2/M phase(P＜0.01).Partial cancer cells presented apoptosis(P＜0.05).Matrine could decrease in the levels of Bcl-2 and increase in the levels of Bax in cell lineLNCaP in a dose-dependent manner(P＜0.01).Matrine could decrease in the levels of ARin cell line LNCaP in a dose-dependent manner(P＜0.01).Matrine inhibited the expressionof PSA on prostate cancer cells(P＜0.05).
Conclusions:Matrine could suppress the growth of LNCaP,and promotes their apoptosis.Matrine also inhibited the expression of AR and PSA on prostate cancer cells.
Key words:prostate cancer;matrine;LNCaP cells;androgen receptor;prostate specific antigen
引文
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[9] Wiwanitkit V. Prostate specific antigen for screening for prostate cancer: an appraisal of Thai reports [J]. Asian Pac J Cancer Prev., 2004, 5 (4): 406-408.
[10] Kim J, Coetzee GA. Prostate specific antigen gene regulation by androgen receptor [J]. J Cell Biochem, 2004, 93 (2):233-241.
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1 Ohmiya S. Stereochemistry, syntheses and biological activity of lupine alkaloids—from studies on the leguminous plants growing mainly in Japan. Yakugaku Zasshi, 2007,127 (10): 1557-1577.
2 Zhang MJ, Huang J. Recent research progress of anti-tumor machnism matrine. Zhongguo Zhong Yao Za Zhi (Chinese), 2004, 29 (2): 115-118.
3 Shrikhande SV, Kleeff J, Kayed H, et al. Silencing of X-linked inhibitor of apoptosis (XIAP) decreases gemcitabine resistance of pancreatic cancer cells. Anticancer Res, 2006,26 (5): 3265-3273.
4 Kem(?)ny-Beke A, Ber(?)nyi E, Facsk(?) A, et al. Antiproliiferative effect of 4-thiouridylate on OCM-1 uveal melanoma cells. Eur J Ophthalmol, 2006, 16 (5): 680-685.
5 Ko YJ, Devi GR, London CA, et al. Androgen receptor down-regulation in prostate cancer with phosphorodiamidate morpholino antisense oligomers. J Urol, 2004, 172 (3): 1140-1144.
6 Yang L, Zhang LY, Chen WW, et al. Inhibition of the expression of prostate specific antigen by curcumin. Yao Xue Xue Bao (Chinese), 2005, 40 (9): 800-803.
7 Hoque A, Chen H, Xu XC. Statin induces apoptosis and cell growth arrest in prostate cancer cells. Cancer Epidemiol Biomarkers Prev, 2008,17 (1): 88-94.
8 Alberti C. Prostate cancer progression and surrounding microenvironment. Int J Biol Markers, 2006, 21 (2): 88-95.
9 Iero M, Pilla L, Marrari A, et al. Vaccination therapy in prostate cancer. Cancer Immunol Immunother, 2007,56 (4): 429-445.
10 Richter E, Srivastava S, Dobi A. Androgen receptor and prostate cancer. Prostate Cancer Prostatic Dis, 2007, 10 (2): 114-118.
11 Agoulnik IU, Weigel NL. Androgen receptor action in hormone-dependent and recurrent prostate cancer. J Cell Biochem, 2006, 99 (2): 362-372.
12 Kageyama Y, Hyochi N, Kihara K, et al. The androgen receptor as putative therapeutic target in hormone-refractory prostate cancer. Recent Patents Anticancer Drug Discov,2007, 2 (3): 203-211.
13 Chmelar R, Buchanan G, Need EF, et al. Androgen receptor coregulators and their involvement in the development and progression of prostate cancer. Int J Cancer, 2007,120 (4): 719-733.
14 Singh P, Uzgare A, Litvinov I, et al. Combinatorial androgen receptor targeted therapy for prostate cancer. Endocr Relat Cancer, 2006,13 (3): 653-666.
15 Ross JS. The androgen receptor in prostate cancer: therapy target in search of an integrated diagnostic test. Adv Anat Pathol, 2007, 14 (5): 353-357.
16 Fournier G, Valeri A, Mangin P, et al. Prostate cancer: Diagnosis and staging. Ann Urol, 2004, 38 (5):207-224.
17 Wiwanitkit V. Prostate specific antigen for screening for prostate cancer: an appraisal of Thai reports. Asian Pac J Cancer Prev., 2004, 5 (4): 406-408.
18 Kim J, Coetzee GA. Prostate specific antigen gene regulation by androgen receptor. J Cell Biochem, 2004, 93 (2):233-241.
19 Taplin ME, Balk SP. Androgen receptor: a key molecule in the progression of prostate cancer to hormone independence. J Cell Biochem, 2004, 91 (3): 483-490.
20 Ma LD, Zhang Y, Wen SH, et al. Inhibition of tumor growth in tumor-bearing mice treated with matrine. Zhonghua Zhong Liu Za Zhi (Chinese), 2005, 27(6): 339-341.
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