15-氧代绣线菊内酯对人肾细胞癌ACHN细胞裸鼠移植瘤生长的影响

Inhibitory effect of 15-oxospiramilactone on the xenograft growth of ACHN human renal carcinoma cells in nude mice

目的肾细胞癌是一种常见恶性肿瘤,化疗和放疗效果均不佳。Wnt信号通路在肾细胞癌的发生,增殖及凋亡等方面起到至关重要的作用。文中旨在研究一种新型小分子wnt信号抑制剂15-氧代绣线菊内酯(NC043)对小鼠肾细胞癌模型的抑制作用。方法将1×107的ACHN人肾癌细胞株在100μL的PBS中混匀,接种于BALB/c雌性裸鼠背部右后侧皮下制作移植瘤模型。成瘤裸鼠按随机列表法分为阴性对照组、NC043 45μg/kg组和NC043 90μg/kg组,后2组按不同浓度NC043溶解于含3%二甲基亚砜DMSO的磷酸盐缓冲液PBS中。3组各连续腹腔注射NC043 15天,第16天处死小鼠。检测各组小鼠的体重和肿瘤体积变化,用免疫组化检测肿瘤细胞的ki67、TCF4和β-catenin表达情况。结果 NC043使得小鼠的肿瘤生长速度明显减缓,体积明显减小,NC043 45μg/kg组和NC043 90μg/kg组抑瘤率分别为36.4%和56.4%,与阴性对照组(0)差异均有统计学意义(P<0.05)。免疫组化检测表明,NC043 90μg/kg组ki67、TCF4、β-catenin表达呈弱阳性,NC04345μg/kg组呈阳性,而阴性对照组呈强阳性。结论 NC043能够有效地抑制肾癌细胞ACHN细胞裸鼠移植瘤的生长,并且抑制Wnt信号通路的相关蛋白的表达,具有潜在的靶向治疗肾癌的作用。

Objective Renal cell carcinoma （RCC） is a common renal malignancy, which is resistant to nearly all chemo- therapeutics and radiotherapy. Wnt signaling plays an important role in the tumorigenesis and cell proliferation and apoptosis of RCC. This study was to explore the inhibiting effect of 15-oxospiramilaetone NC043, a new Wnt molecule inhibiter, on the xenograft growth of human renal carcinoma （ACHN） cells in nude mice. Methods ACHN cells （ 1 × 107 ） were suspended in 100μL PBS and injec- ted subcutaneously into the fight side of the posterior flank of female BALB/e athymie nude mice to establish a xenograft model. The nude mice bearing ACHN cells were randomly divided into three groups, negative control, low-dose medication, and high-dose medica- tion, treated by daily intraperitoneal injection of 3 % DMSO, NC043 at 45 μg/kg, and NC043 at 90μg/kg, respectively, for 15 days. At 16 days, all the mice were killed, the body weight and tumor volume obtained, and the expressions of ki67, TCF4 and β-catenindetermined by immunohistochemistry. Results NC043 significantly inhibited the growth of the xenograft tumor, with an inhibition rate of 36.4% in the 45 μg/kg group and 56.4% in 90 μg/kg group. The expressions of ki67, TCF4, and β-eatenin were markedly down-regu- lated in a dose-dependent manner （ P 〈 0. 01 ）. Conclusion NC043 can effectively suppress the growth of ACHN cells in the xeno- graft tumor and reduce the expression of Wnt-related proteins, andtherefore is a potential compound for the treatment of renal cell carcinoma.