| 苯乙双胍联合己糖激酶抑制剂诱导三阴性乳腺癌细胞凋亡 |
| 投稿时间：2021-03-19 修订日期：2021-07-06 点此下载全文 |
| 引用本文：叶琳岚,贺春晖,朱旭婷,李霞.苯乙双胍联合己糖激酶抑制剂诱导三阴性乳腺癌细胞凋亡[J].药学实践杂志,2022,40(3):248~253 |
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| 基金项目:2020年度无锡市科技发展资金项目（N20202027） |
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| 中文摘要:目的 探讨降糖药物苯乙双胍联合己糖激酶抑制剂2-脱氧葡萄糖（2-DG）对三阴性乳腺癌细胞4T1和MDA-MB-231凋亡作用的影响。方法 苯乙双胍单独或联合2-DG处理4T1与MDA-MB-231细胞48 h，用SRB法检测细胞的增殖，流式细胞术检测细胞凋亡，试剂盒检测培养上清液中葡萄糖消耗量和乳酸含量，多功能化学发光仪检测线粒体呼吸链复合物I活性，海马能量检测仪测定细胞线粒体耗氧量(OCR)。结果 苯乙双胍组的4T1与MDA-MB-231细胞上清液己糖激酶表达量（4.6±0.17，3.73±0.21），葡萄糖消耗量（356±31，397±42）μg/105个细胞，乳酸浓度（5.59±0.52，7.83±0.78）μmol/L均高于空白组的已糖激酶表达量（1±0.15，1±0.12），葡萄糖消耗量（289±25，301±32）μg/105个细胞，乳酸浓度（2.37±0.18，4.01±0.45）μmol/L（P < 0.01）；苯乙双胍联用2-DG组的细胞存活率（64.63±2.28，51.97±2.29）% ，即使降低90%剂量，仍高于苯乙双胍组（86.70±1.83，85.53±1.46）%（P<0.001），两药联用极大地促进了4T1与MDA-MB-231细胞的凋亡，此外，相比于苯乙双胍组（5.59±0.52，7.83±0.78）μmol/L，苯乙双胍与2-DG联用组（3.46±0.37，5.18±0.62）μmol/L细胞的乳酸产量也大大下降（P<0.01）；与苯乙双胍或2-DG单药组相比，苯乙双胍联合2-DG组可显著抑制荷瘤小鼠体内肿瘤的生长速度（P<0.01）；苯乙双胍联合2-DG组荷瘤小鼠中位生存时间72.5 d，高于苯乙双胍组57 d、2-DG组55.5 d（P<0.01），苯乙双胍联合2-DG可以延长荷瘤小鼠生存时间。结论 己糖激酶抑制剂2-DG显著增强了苯乙双胍对三阴性乳腺癌细胞的治疗作用。 |
| 中文关键词:苯乙双胍 三阴性乳腺癌 2-脱氧葡萄糖 氧化磷酸化 有氧糖酵解 |
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| Hexokinase inhibitor 2-deoxyglucose combined with phenformin induces cell apoptosis of triple-negative breast cancer |
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| Abstract:Objective To investigate the effect of phenformin combined with hexokinase inhibitor 2-deoxyglucose (2-DG) on the treatment of triple-negative breast cancer cell lines 4T1 and MDA-MB-231. Methods Following treatment with phenformin, 2-DG or phenformin combined with 2-DG on 4T1 and MDA-MB-231 cells for 48 h, the cell proliferation in each group was detected by SRB and the apoptosis of cells was detected by flow cytometry. The concentration of glucose and lactic acid in cell culture supernatant was detected by ELISA. The activity of mitochondrial respiratory chain complex Ⅰ was detected by FlexStation3 and the mitochondrial oxygen consumption (OCR) was assayed with the Seahorse X Fe Analyzer. Results The hexokinase expression (4.6±0.17,3.73±0.21), glucose consumption (356±31，397±42) μg/105 cells , Lactic acid concentration (5.59±0.52, 7.83±0.78) μmol/L in the supernatant of 4T1 and MDA-MB-231 cells in Phenformin group were higher than that in control group ( 1±0.15，1±0.12 ) , ( 289±25，301±32) μg/105cells , ( 2.37±0.18，4.01±0.45) μmol/L (P < 0.01). Even if the dose was reduced by 90%, the cell viability of phenformin combined with 2-DG group (64.63±2.28, 51.97±2.29) % was still higher than that of phenformin group (86.70±1.83, 85.53±1.46) % (P<0.001). The combination of the two drugs significantly promoted the apoptosis of 4T1 and MDA-MB-231. In addition, compared with the phenformin group (5.59±0.52, 7.83±0.78) μmol/L, the phenformin combined with 2-DG group (3.46±0.37, 5.18±0.62) μmol/L cell lactic acid production also greatly reduced (P<0.01). Compared with the phenformin or 2-DG single-drug group, the phenformin combined with 2-DG group can significantly inhibit the growth rate of tumors in tumor-bearing mice (P<0.01). The median survival time of tumor-bearing mice in the phenformin combined with 2-DG group was 72.5 d, which was higher than that in the phenformin group 57 d and 2-DG group 55.5 d (P<0.01). Conclusion Hexokinase inhibitor 2-DG significantly enhances the therapeutic effects of phenformin on triple-negative breast cancer cells. |
| keywords:phenformin triple-negative breast cancer 2-deoxyglucose oxidative phosphorylation aerobic glycolysis |
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