丹参酮ⅡA对小鼠肠癌皮下移植瘤血管新生的抑制作用

Tanshinone IIA inhibits angiogenesis in subcutaneous colorectal cancer xenografts in mice

目的:探讨中药丹参活性成分TanⅡA对肠癌小鼠皮下移植瘤微血管生成的抑制作用.方法:通过腋下接种小鼠C26肠癌细胞,建立小鼠结肠癌移植瘤模型,随机分为:模型组、TanⅡA低[0.5mg/(kg·d)]、中[1mg/(kg·d)]、高[2mg/(kg·d)]剂量组、5-氟脲嘧啶[1mg/(kg·d)]组,经尾静脉分别给予生理盐水、不同浓度的TanⅡA及5-氟脲嘧啶,每天1次,给药1wk.给药7d后摘除眼球取血,剥离瘤体,测量大小及质量.免疫组织化学法检测MVD,HE染色检测肿瘤组织坏死情况,ELISA法检测小鼠血清VEGF的表达.结果:TanⅡA低、中、高剂量的肿瘤质量抑制率分别为:45.8%、60.3%及84.5%,肿瘤体积抑制率为:50.5%、60.7%及84.2%;模型组与低剂量组肿瘤组织以轻度坏死为主,MVD值分别为:86.5±14.6与73.5±19.8,中、高剂量组则以中、重度坏死为主,MVD值分别为:48.6±15.2与19.4±6.6;模型组血清VEGF的浓度显著高于空白组,TanⅡA低、中、高剂量组VEGF抑制率分别为:15.8%、34.2%及74.8%.结论:TanⅡA能够抑制小鼠肠癌微血管生成,并对肠癌的生长有明显抑制作用,其抗肠癌作用与抑制VEGF、MVD有关.

AIM： To investigate the effects of tanshinone IIA （an active component of traditional Chinese medicine salvia miltiorrhiza） on angiogenesis in subcutaneous colorectal cancer xenografts in mice. METHODS： An ectopic mouse model of colorectal cancer was established by subcutaneously inoculating colon carcinoma C26 cells into the armpit of mice. The mice were then randomly divided into 5 groups： model control group, low-dose tanshinone IIA group [0.5 mg/（kg·d）], mid-dose tanshinone IIA group [1 mg/（kg·d）], high-dose tanshinone IIA group [2 mg/（kg·d）], and 5-fluorouracil（5-FU） group [1 mg/（kg·d）]. Normal saline （model control group）, tanshinone IIA of different doses and 5-FU were injected via the vena caudalis once daily for one week, respectively. Seven days later, the eyeballs were removed to collect blood samples, and the tumors were peeled off to measure tumor size and weight. The microvessel density （MVD） was tested by immunohistochemistry. Tumor necrosis was detected by hematoxylin and eosin staining. Serum VEGF level was assayed by enzyme-linked immunosorbent assay （ELISA）. RESULTS： Compared with the model control group, tumor weight decreased by 45.8%, 60.3% and 84.5% in the low-, mid- and high-dose tan- shinone IIA groups, respectively. Correspond- ing tumor size decreased by 50.5%, 60.7% and 84.2%, respectively. Tumor necrosis was mild in the model control group and low-dose tanshinone IIA group, but moderate to severe in the mid- and high-dose tanshinone IIA groups. The MVD was higher in the model control group and low-dose tanshinone IIA group than in the mid- and high-dose tanshinone IIA groups （86.5 ± 14.6 and 73.5 ± 19.8 vs 48.6 ± 15.2 and 19.4 ± 6.6, respectively）. Serum VEGF level was signifi cantly higher in the model control group than in the normal control group. Compared to the model control group, serum VEGF levels decreased by 15.8%, 34.2% and 74.8% in the low-, mid- and high-dose tanshinone IIA groups, respectively. CONCLUSION： Tanshinone IIA can inhibit tumor angiogenesis and growth of colorectal cancer xenografts in mice perhaps via inhibition of VEGF and MVD.