雷公藤红素抑制可移植性人脑胶质瘤生长相关分子

Celastrol inhibits human glioma xenograft

目的研究雷公藤红素在裸鼠胶质瘤动物模型治疗人脑胶质瘤的可行性。探讨雷公藤红素抑制SHG-44胶质瘤裸鼠移植瘤生长的作用机制。方法建立BALB/c裸小鼠SHG-44胶质瘤移植瘤模型,将荷瘤裸鼠随机分为5组,采用腹腔内注射给药方法。雷公藤红素按4mg/kg、2mg/kg、1mg/kg三种浓度分组给药;阳性对照顺铂组按2mg/kg给药。定期观察肿瘤生长情况测量肿瘤体积,绘制肿瘤生长曲线并计算抑瘤率。全部SHG-44裸鼠移植瘤石蜡标本用SP法免疫组化染色,检测移植瘤组织中的微血管计数(MVD)、以及bFGF、周期蛋白D1和PCNA的蛋白表达。结果与溶媒对照组相比,雷公藤红素4mg/kg组、2mg/kg组均能抑制肿瘤生长(P<0·05),其体积抑瘤率分别为35%和26·9%。雷公藤红素高剂量组能下调移植瘤组织中bFGF的蛋白表达(P<0·05);MVD也随之降低(P<0·05),呈剂量依赖关系。PCNA、周期蛋白D1在雷公藤红素高、中剂量组及阳性对照组移植瘤中的蛋白表达明显低于溶媒对照组(P<0·05),呈剂量依赖关系。结论雷公藤红素能明显抑制SHG-44裸鼠移植瘤生长,并存在剂量依赖性。其机制可能是下调bFGF的蛋白表达,抑制肿瘤血管生成,下调周期蛋白D1、PCNA的蛋白表达,对肿瘤细胞周期进行调控。

Objective To investigate the effects of celastrol on the growth of human malignant glioma cell line SHG-44 in vivo and study the mechanism that celastrol inhibits the growth of a human malignant glioma cell line SHG-44 in vivo. Methods Animal models were established on BALB/c nude mice with subcutaneously transplanted neoplasma of SHG-44 glioma. The nude mice bearing with SHG44 glioma were devided randomly into five groups, which were treated without drugs or with different doses of celastrol（4 mg/kg,2 mg/kg and 1 mg/kg） or with cisplatin（2 mg/kg）. The dimension of xenografts was measured and the living state of nude mice with SHG-44 glioma was observed. The protein expression of microvessel density（MVD）, bFGF, cyclin D1, PCNA in each paraffin imbedded xenograft of nude mice bearing with SHG-44 glioma were detected by immunohistoehemistry staining. Results Celastrol at both 4 mg/kg and 2 mg/kg inhibited the growth of xenografts in nude mice with SHG44 blioma（P〈0. 05） ,and the tumor volume was reduced by 35% and 26. 9% in both of celastroltreated groups respectively compared with that in the dissolvent control. Meanwhile the control group highly expressed bFGF at the level of protein, coupling with increase of MVD. Compared with the dissolvent control group,two groups of celastrol 4 mg/kg and 2 mg/kg showed lower expression of them （P〈0. 05） and more decrease in MVD（P〈0.05）. The protein expression of PCNA and cyclin D1 in two groups of celastrol 4 mg/kg and 2 mg/kg was dose dependently lower than that in control group （P〈0. 05）. Conclusion Celastrol can inhibit the growth of a human malignant glioma cell line SHG- 44 in vivo significantly and dose-dependently. Celastrol can significantly suppress the expression of bFGF,PCNA and cyclin D1 at the level of protein. The mechanism of supressing glioma may be a down-regulation of protein expression of bFGF resucting in the inhibition of angiogenesis. In virtue of regulating cell-cycle, the down-regulation of PCNA and cyclin D1 protein expression may suppress the proliferation of neoplasma.