多沙唑嗪对前列腺癌裸鼠移植瘤的抑制作用

目的:探讨α1肾上腺素能受体拮抗剂多沙唑嗪对雄激素非依赖性前列腺癌细胞系PC-3在裸鼠体内生长的影响及其作用机制.方法:建立前列腺癌细胞系PC-3的裸鼠体内移植瘤模型,将30只荷瘤裸鼠随机分为5组A组(对照组),B组(多沙唑嗪3 mg/kg),C组(多沙唑嗪10 mg/kg),D组(多沙唑嗪30 mg/kg),E组(多沙唑嗪100mg/kg)].接种肿瘤细胞1周后每天1次灌胃给药,每周测量肿瘤体积2次,给药2周后处死裸鼠,取肿瘤组织做免疫组织化学Ki67及细胞凋亡DNA原位标记法(TUNEL法)检测,并用免疫印迹法研究蛋白Smad-4及IκBα在各组肿瘤组织中的表达情况.结果:多沙唑嗪给药组肿瘤体积较对照组显著缩小,肿瘤的重量较对照组亦显著减轻,而不同剂量的多沙唑嗪给药组间肿瘤大小差异无统计学意义.免疫组织化学结果显示前列腺癌细胞Ki67的阳性率在A至E组依次为36.5%±8.5%,37.7%±11.3%,40.1%±12.7%,37.2%±12.3%,39.3%±13.1%,各组间差异无统计学意义(P＞0.05);而前列腺癌细胞的TUNEL阳性率在A至E组依次为9.5%±3.5%,24.7%±8.3%,25.7%±9.7%,28.2%±12.1%,27.5%±11.3%,各用药组明显高于对照组(P＜0.01);免疫印迹结果表明用药组蛋白Smad-4及IκBα的表达显著高于对照组.结论:α1肾上腺素能受体拮抗剂多沙唑嗪对雄激素非依赖性前列腺癌细胞PC-3裸鼠体内移植瘤的生长具有明显抑制作用,其作用机制可能是药物诱导了前列腺癌细胞凋亡,对细胞的增殖并没有明显的影响;而TGF-β1信号转导通路的激活可能是多沙唑嗪引起前列腺癌细胞凋亡的重要机制.

Inhibitory effect of doxazosin on the growth of transplanted tumor of prostate cancer cell PC-3 in nude mice

OBJECTIVE: To investigate the effects of alpha1 adrenoceptor antagonist doxazosin on the growth of androgen-independent prostate cancer cell PC-3 transplanted in nude mice. METHODS: PC-3 cells xenografts were transplanted (s.c.) in nude mice, and thirty xenografts were established successively. They were then randomly divided into 5 groups: A (control group), B (doxazosin 3 mg/kg), C (doxazosin 10 mg/kg), D (doxazosin 30 mg/kg), and E (doxazosin 100 mg/kg). Seven days after implantation, doxazosin was administered in sterile water by oral gavage, and the volumes of the transplanted tumors were measured during the therapy twice a week. All the mice were sacrificed after two weeks of doxazosin administration; the tumors were resected to do the following research. Immunohistochemistry of Ki67 and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling (TUNEL) was done to study the effects of doxazosin on the proliferation and apoptosis of prostate cancer cells; moreover, we also used Western blotting to study the protein expression of Smad-4 and IkappaB alpha. RESULTS: Nude mouse experiments showed that the in vivo doxazosin administration induced a notable decrease in the volumes of prostate cancer xenografts compared with the control group, and the tumor weights were also decreased. Interestingly enough, administration of doxazosin at higher concentrations (10, 30, 100 mg/kg) did not have further effect on tumor suppression. The percentage of PC-3 TUNEL positive cells was significantly higher than that of the control group; while the doxazosin treated groups and the control group did not have statistical difference on the percentage of Ki67 positive cells. In doxazosin treated groups Smad-4 and IkappaB alpha expressions were higher than that of the control group. CONCLUSION: Doxazosin can inhibit the growth of the prostate xenografts in the nude mice by inducing apoptosis without affecting the cell proliferation. Activation of transforming growth factor beta1 (TGF-beta1) signaling pathway may be the mechanism underlying doxazosin-mediated apoptosis.