四氢异喹啉类化合物HZ08通过降低白血病细胞的葡萄糖神经酰胺合成酶和MDR1表达水平逆转耐药作用
HZ08 reverses multidrug resistance in leukemia cells by reducing glucosylceramide synthase and MDR1
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摘要: 通过对比K562/A02细胞株和耐药白血病临床样本的实验结果，探讨四氢异喹啉类化合物HZ08对多药耐药的逆转作用和逆转机制。将阿霉素与10 μmol/L HZ08合用，MTT法测得阿霉素对临床耐药的白血病细胞的IC5为0.60 μmol/L，对K562/A02细胞的IC50为0.83 μmol/L，逆转倍数分别为27.87和20.49。使用免疫印迹法检测细胞内葡萄糖神经酰胺合成酶（GCS）表达水平，荧光实时定量聚合酶链反应检测MDR1的mRNA表达水平。结果显示：各浓度的HZ08（15，20，25 μmol/L)与阿霉素合用均能降低GCS的表达，与单用阿霉素组相比，阿霉素与HZ08合用可显著降低MDR1的mRNA表达(P<0.01)至空白组水平。结果表明，HZ08与阿霉素合用给药，对K562/A02细胞株和耐药的临床耐药白血病细胞均有较强的逆转作用，其机制可能与降低细胞内GCS蛋白的表达和MDR1 mRNA的表达有关。
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关键词:
- 多药耐药 /
- 葡萄糖神经酰胺合成酶 /
- K562/A02细胞 /
- 慢性粒细胞性白血病
Abstract: In this paper the influence of HZ08 on multidrug resistance and possible mechanism were explored.It was found that the IC50of adriamycin in the presence of 10 μmol/L HZ08 in clinical sample cells was 0.60 μmol/L,while the IC50in K562/A02 cells was 0.83 μmol/L by MTT.The reversal folds of MDR were 27.87 and 20.49,respectively.For further mechanism study of HZ08,the expression level of glucosylceramide synthase (GCS) protein in K562/A02 and resistant cells from clinical samples were analyzed by Western blot,while the mRNA of MDR1 was detected by real-time fluorescent quantitative polymerase chain reaction (FQ-RT-PCR).Combined with adriamycin,all concentrations (15,20,25 μmol/L) of HZ08 decreased the expression of GCS protein.In addition,compared with the group of treatment with adriamycin alone,combined treatment of HZ08 and adriamycin decreased the expression of MDR1 significantly (P<0.01).Therefore,HZ08 possibly reverses multidrug resistance by its joint action with adriamycin on GCS and MDR1 in both cell line and clinical sample cells. -
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