三氧化二砷联合5-FU抑制结肠癌干细胞的研究

The evaluation of 5-FU in combination with As_2O_3 for colorectal cancer treatment

目的探讨三氧化二砷(As2O3)联合5-氟尿嘧啶(5-FU)对结肠癌干细胞的抑制作用。方法将结肠癌干细胞分成As2O3干预组、5-FU干预组、联合干预组和PBS阴性对照组。采用MTT实验考察联合干预对结肠癌干细胞的毒性。用结肠癌干细胞构建肿瘤球模型,考察联合干预对结肠癌干细胞肿瘤球的生长抑制作用。采用流式细胞技术考察联合干预诱导肿瘤干细胞凋亡的能力。制备结肠癌的动物模型,考察联合干预对结肠癌荷瘤小鼠肿瘤的抑制作用。结果与PBS组和单独给药组相比,联合干预组对结肠癌干细胞具有更强的细胞毒性,差异具有统计学意义(P<0.01)。细胞凋亡实验结果表明,联合干预能够促进肿瘤干细胞凋亡,差异具有统计学意义(P<0.01)。肿瘤球给药7 d后5-FU干预组、As2O3干预组和联合干预组分别使肿瘤体积减小到原体积的71%、85%和44%,PBS组肿瘤球体积增大1.48倍,差异具有统计学意义(P<0.01);体内治疗实验结果显示,PBS组、As2O3干预组和5-FU干预组小鼠肿瘤体积成长分别变为给药前肿瘤体积的2.55倍、2.13倍和1.54倍,而联合干预组肿瘤体积变化为原体积的1.27倍,联合干预组与环靶明干预组或5-FU干预组间差异具有统计学意义(P<0.01)。结论 As2O3联合5-FU能够有效抑制结肠癌干细胞的增殖,5-FU联合As2O3是一种潜在的结肠癌干细胞治疗方法。

Objective To evaluate the effect of 5-FU combined with As2O3 the inhibition of colorectal cancer stem cells （LSCs）.Methods The colorectal cancer stem cells were divided into four groups：As2O3 group,5-FU group,As2O3 ＋ 5-FU group and PBS group.The MTT assay was used to evaluate the anti-proliferation efficiency of As2O3 combined with 5-FU.Flow cytometry was used to evaluate the LSCs induced apoptosis by 5-FU and As2O3.Tumor spheroids were also used to evaluate anti-tumor ability of 5-FU combined with As2O3.LSCs were xenografted in mice to establish the animal model,which were used to evaluate the effect of anti-tumor.Results Compared with PBS group,5-FU group and As2O3 group,the As2O3 ＋ 5-FU group could inhibit the growth of LSCs effectively （P ＜ 0.05）.The 5-FU combined with As2O3 could induced the apoptosis of LSCs more effective than As2O3 alone.The As2O3 ＋ 5-FU group could significantly inhibit the growth of tumor.Conclusion The As2O3 can inhibit the growth of colorectal cancer stem cells,the As2O3 ＋ 5-FU can induce the apoptosis of LSCs,and the combination of As2O3 and 5-FU may be a potentially effective treatment for colorectal cancer.