乳腺癌细胞的HER2过表达降低其对紫杉醇的药物敏感性

目的紫杉醇的耐药性由多种因素引起,本文研究乳腺癌细胞中的HER2蛋白水平是否影响细胞对紫杉醇的药物敏感性。方法以HER2低表达的MCF-7/pcDNA3.1细胞和经稳定转染获得的HER2高表达的MCF-7/HER2细胞为研究对象,MTT方法测定紫杉醇对这两种细胞的生长抑制作用,流式细胞仪测定紫杉醇对细胞周期分布的影响,An-nexin V-FITC/PI实验测定紫杉醇诱导的细胞凋亡,两种细胞的裸鼠移植瘤实验测定紫杉醇的抑瘤率。结果紫杉醇对MCF-7/HER2细胞的IC50值是MCF-7/pcDNA3.1细胞的6.2倍;紫杉醇诱导细胞G2/M期阻滞,且是HER2非依赖性的;0.01、0.1和1.0μmol.L-1紫杉醇诱导MCF-7/pcDNA3.1细胞凋亡的百分比分别是15.1%±2.1%、21.0%±2.9%和35.7%±3.8%,诱导MCF-7/HER2细胞凋亡的百分比分别是7.5%±1.7%、14.1%±2.3%和24.2%±3.4%,同一浓度的紫杉醇诱导两细胞的凋亡百分比差异有显著性;5、10和20 mg.kg-1的紫杉醇对裸鼠移植MCF-7/pcDNA3.1肿瘤生长抑制率分别是36.9%、58.7%和75.4%,对裸鼠移植MCF-7/HER2肿瘤生长抑制率分别是20.1%、33.3%和67.3%。在相同剂量下紫杉醇对裸鼠移植的两种肿瘤的抑瘤率差异有显著性。结论HER2蛋白的高表达可降低乳腺癌细胞对紫杉醇的药物敏感性。

HER2 overexpression in breast cancer cells reduces the sensitivity to taxol

Aim To investigate the effects of HER2 overexpression on the chemosensitivity of breast cancer cells to taxol.Methods MTT assay was used to determine the growth inhibition of taxol in both of HER2 low-expressing MCF-7/pcDNA3.1 cells and HER2 overexpressing MCF-7/HER2 cells.The effect of taxol on cell cycle distribution in both cells was detected by flow cytometry.Annexin V-FITC/PI was performed to analyze apoptotic cells.Tumor growth inhibitory effects of taxol were examined in nude mice bearing MCF-7/pcDNA3.1 or MCF-7/HER2 xenograft.Results MTT assay showed that MCF-7/HER2 cells were more resistant than MCF-7/pcDNA3.1 cells to taxol with IC50 values of(0.074±0.012) μmol·L-1 and(0.461±0.035) μmol·L-1,respectively.Both cells were arrested at G2/M phase without significant differences after exposure to taxol.The apoptotic fraction in MCF-7/pcDNA3.1 cells was significantly higher than that inMCF-7/HER2 cells after being treated with taxol.At the dose of 5,10 and 20 mg·kg-1 taxol,tumor growth was inhibited by 36.9%,58.7% and 75.4% in nude mice bearing MCF-7/pcDNA3.1 xenograft,and inhibited by 20.1%,33.3% and 67.3% in nude mice bearing MCF-7/HER2 xenograft,respectively.Conclusions These results demonstrate that HER2 overexpression in breast cancer cells may reduce the sensitivity to taxol.