[关键词]
[摘要]
目的 探讨蝎毒多肽增强5-氟尿嘧啶(5-Fu)对肝癌H22抑制作用的机制。方法 以接种H22肝癌小鼠腹水方法建立小鼠荷瘤模型,在接种后第7天将荷瘤小鼠随机分为模型组、蝎毒多肽(20 mg/kg)组、5-Fu(15 mg/kg)组、低剂量蝎毒多肽(5 mg/kg)+5-Fu组、高剂量蝎毒多肽(20 mg/kg)+5-Fu组,每组10只,连续给药21 d。绘制肿瘤体积增长曲线并计算抑瘤率;CD34标记肿瘤微血管;免疫组织化学法检测核因子-κB(NF-κB)、基质金属蛋白酶-9(MMP-9)和血管内皮生长因子(VEGF)蛋白表达。结果 与模型组相比,联合给药组H22肝癌移植瘤的生长受到明显抑制(P<0.01),微血管密度(MVD)及NF-κB、MMP-9、VEGF蛋白表达均明显降低(P<0.01);与5-Fu组相比,高剂量蝎毒多肽+5-Fu组的MVD及NF-κB、MMP-9、VEGF蛋白表达也显著降低(P<0.01),而低剂量蝎毒多肽+5-Fu组则无显著改变。结论 蝎毒多肽可增加5-Fu对肿瘤组织的抑制作用,其机制可能与抑制H22肝癌组织NF-κB通路及MMP-9、VEGF的表达,从而抑制新生血管形成有关。
[Key word]
[Abstract]
Objective To explore the mechanism of polypeptide from scorpion venom (PSV) on increasing the inhibition of 5-fluorouacil (5-Fu) on H22 hepatoma. Methods H22 hepatoma model was established through sc inoculating H22 cells suspension into 40 mice in right armpits. Then tumor-bearing mice were divided into five groups randomly on the day 7 after inoculating: model, PSV (20 mg/kg), 5-Fu (15 mg/kg), low-dose PSV (5 mg/kg) + 5-Fu, and high-dose PSV (20 mg/kg) + 5-Fu groups, 10 mice in each group, continuously admininstered for 21 d. Tumor volumes were measured once every other day, then the curves of tumor growth were drawn and the tumor inhibitory rate was calculated; CD34 was used to mark capillary; Immunohistochemical assay was used to detect the protein expression changes of nuclear factor-kappa B (NF-κB), matrix metalloproteinase-9 (MMP-9), and vascular endothelial growth factor (VEGF). Results Compared with the model group, the growth of H22 hepatoma transplantation tumor in the combinational groups was obviously inhibited (P < 0.01); The microvessel density (MVD) and the protein expression of NF-κB, MMP-9, and VEGF in the two PSV groups were all decreased significantly (P < 0.01); Compared with 5-Fu group, the MVD and the protein expression of NF-κB, MMP-9, and VEGF in the high-dose PSV + 5-Fu group were also decreased (P < 0.01), while there was no significant difference between the low-dose PSV + 5-Fu group. Conclusion PSV may increase the inhibition of 5-Fu on H22 hepatoma through blocking NF-κB pathway and reducing the expression of MMP-9 and VGF, which is beneficial to the inhibition of angiogenesis.
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[基金项目]
国家自然科学基金资助项目(81073102,30873408);山东省自然科学基金资助项目(ZR2010HQ003);济南市科学技术发展计划(201004012)