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非甾体类抗炎药物(nonsteroidal anti-inflammatory drugs,NSAIDs)能增强化疗药物对肿瘤细胞的细胞毒性作用。该研究首先筛选出无细胞毒性剂量的吲哚美辛,采用MTT法和流式细胞仪分别检测阿霉素或阿霉素联合低剂量吲哚美辛对U251细胞增殖和早期凋亡的影响;并应用RT-PCR和Western blot检测吲哚美辛对ABCG2、MDR1和MRP1的影响。结果显示,20μmol/L吲哚美辛对胶质瘤U251细胞无显著生长抑制(P>0.05),可作为无细胞毒性剂量使用;0.8 mg/L阿霉素组和20μmol/L吲哚美辛联合0.8 mg/L阿霉素组与对照组相比细胞增殖显著下降(P<0.05),且吲哚美辛联合阿霉素组较单独使用阿霉素组的生长抑制作用更为显著(P<0.05);72 h后单独使用阿霉素组和阿霉素联合吲哚美辛组细胞早期凋亡率均增加(P<0.01),但阿霉素联合吲哚美辛组较阿霉素组凋亡率上升更为明显(P<0.05);RT-PCR和Western blot证实吲哚美辛能够下调ABCG2、MDR1和MRP1的表达(P<0.05)且呈现出浓度依赖性。提示吲哚美辛能够增强阿霉素对胶质瘤U251细胞的生长抑制作用,其机制与吲哚美辛下调耐药基因的表达有关。
Nonsteroidal anti-inflammatory drugs (NSAIDs) enhance the cytotoxic effects of chemotherapeutic drugs on tumor cells. In this study, cytotoxic doses of indomethacin were initially screened. The effects of doxorubicin or doxorubicin combined with low-dose indomethacin on the proliferation and early apoptosis of U251 cells were detected by MTT and flow cytometry, respectively. The effects of indomethacin on ABCG2, MDR1 and MRP1 were detected by RT-PCR and Western blot. The results showed that 20μmol / L indomethacin showed no significant inhibitory effect on glioma U251 cells (P> 0.05), and could be used as non-cytotoxic dose; while 0.8 mg / L doxorubicin and 20 μmol / L indomethacin Compared with the control group, the cell proliferation of the combined 0.8 mg / L doxorubicin group was significantly decreased (P <0.05), and the indomethacin combined with doxorubicin group was more significant than the doxorubicin alone group (P <0.05). After 72 h, the apoptotic rates of adriamycin alone and doxorubicin plus indomethacin groups were significantly increased (P <0.01), but those of doxorubicin plus indomethacin group were higher than those of doxorubicin (P <0.05). RT-PCR and Western blot confirmed that indomethacin down-regulated the expression of ABCG2, MDR1 and MRP1 (P <0.05) in a concentration-dependent manner. These results suggest that indomethacin can enhance the suppressive effect of doxorubicin on glioma U251 cells by down-regulating the expression of drug resistance genes.