Abstract

Insulin resistance promotes the occurrence of liver cancer and decreases its chemosensitivity. Rosiglitazone (ROSI), a thiazolidinedione insulin sensitiser, could be used for diabetes with insulin resistance and has been reported to show anticancer effects on human malignant cells. In this paper, we investigated the combination of ROSI and chemotherapeutics on the growth and metastasis of insulin-resistant hepatoma. In vitro assay, ROSI significantly enhanced the inhibitory effects of adriamycin (ADR) on the proliferation, autophagy and migration of insulin-resistant hepatoma HepG2/IR cells via downregulation of EGFR/ERK and AKT/mTOR signalling pathway. In addition, ROSI promoted the apoptosis of HepG2/IR cells induced by ADR. In vivo assay, high fat and glucose diet and streptozotocin (STZ) induced insulin resistance in mice by increasing the body weight, fasting blood glucose (FBG) level, oral glucose tolerance, fasting insulin level and insulin resistance index. Both the growth of mouse liver cancer hepatoma H22 cells and serum FBG level in insulin resistant mice were significantly inhibited by combination of ROSI and ADR. Thus, ROSI and ADR in combination showed a stronger anti-tumour effect in insulin resistant hepatoma cells accompanying with glucose reduction and might represent an effective therapeutic strategy for liver cancer accompanied with insulin resistant diabetes.

摘要

胰岛素抵抗促进肝癌的发生并降低其化学敏感性。罗格列酮 (ROSI) 是一种噻唑烷二酮类胰岛素增敏剂，可用于治疗具有胰岛素抵抗的糖尿病，据报道对人类恶性细胞具有抗癌作用。在本文中，我们研究了 ROSI 和化疗药物的组合对胰岛素抵抗性肝癌的生长和转移的影响。体外试验中，ROSI通过下调EGFR/ERK和AKT/mTOR信号通路，显着增强了阿霉素（ADR）对胰岛素抵抗肝癌HepG2/IR细胞增殖、自噬和迁移的抑制作用。此外，ROSI促进ADR诱导的HepG2/IR细胞凋亡。体内实验表明，高脂高糖饮食和链脲佐菌素 (STZ) 通过增加体重、空腹血糖 (FBG) 水平、口服葡萄糖耐量、空腹胰岛素水平和胰岛素抵抗指数来诱导小鼠的胰岛素抵抗。ROSI和ADR联用显着抑制胰岛素抵抗小鼠肝癌H22细胞的生长和血清FBG水平。因此，ROSI 和 ADR 的组合在胰岛素抵抗的肝癌细胞中显示出更强的抗肿瘤作用，伴随着葡萄糖的降低，可能代表了肝癌合并胰岛素抵抗糖尿病的有效治疗策略。