新型斑蝥素类似物LB1协同阿霉素杀伤肝癌细胞的实验研究

Synergistic effect of a novel cantharidin analog LB1 with doxorubicin in chemotherapy against hepatocellular carcinoma cells

目的通过水溶性化学小分子蛋白磷酸酶2A抑制剂LB1与阿霉素(doxorubicin,DOX)联合应用,研究其在肝癌化疗过程中的协同作用。方法体外细胞活性分析检测不同剂量LB1对HepG2细胞活性影响及其与阿霉素(DOX)的协同杀伤效应;通过裸鼠体内荷瘤模型以及组织化学分析,进一步观察LB1对肿瘤生长影响以及在体与阿霉素的协同化疗作用。结果 LB1对HepG2细胞生长与作用剂量相关,低剂量时可促进其生长,高剂量时则促进其凋亡,而且在联合阿霉素后,可显著提高对HepG2肿瘤细胞的杀伤作用;体内实验也发现,单纯给予阿霉素抑瘤率为57%,而LB1联合应用后,抑瘤率可达77%,显著提高了阿霉素对肿瘤的杀伤作用(P<0.05),且无明显毒副作用。结论 LB1联合应用可显著提高阿霉素(DOX)对肝癌细胞的化学杀伤作用。

Objective To investigate the synergistic effect of cantharidin analog LB1,a novel inhibitor of protein phosphatase 2A,with doxorubicin（DOX） on human HepG2 hepatocellular carcinoma cells.Methods In vitro cell viability analysis was applied to detect the effect of different doses of LB1 and the synergistic effect of LB1 with DOX on HepG2 cells.The in vivo synergistic effect of LB1 with DOX was further examined in HepG2 tumor xenografts in athymic nude mice by immunohistochemical assay.Tumor growth and mouse weight were measured after the treatment.Results The effect of LB1 on the growth of HepG2 cells was associated with the doses of administration.Low doses of LB1（10 mol/L） promoted cell viability,while high doses of LB1（10 mol/L） induced the mitotic catastrophe and apoptosis of HepG2 cells.The in vivo experiment results showed that the growth inhibition rate of HepG2 cells was 57% for DOX alone,and increased significantly to 77% for LB1 and DOX combination.LB1 significantly enhanced the effect of DOX on tumor growth inhibition in both cultured HepG2 in vitro and mouse xenografts in vivo without apparent toxicity（P0.05）.Conclusion LB1 can enhance the effect of doxorubicin in the chemotherapy against hepatocellular carcinoma cells.