期刊
CANCER CHEMOTHERAPY AND PHARMACOLOGY
卷 85, 期 2, 页码 331-343出版社
SPRINGER
DOI: 10.1007/s00280-020-04033-z
关键词
HCC; diethylnitrosamine; NLRP3 inflammasome; Metformin; celastrol; I kappa b kappa b; Caspase-1; Apoptosis; NF kappa Bp65; Bax; BCL-2; TLR4; I kappa B alpha
One promising strategy for minimizing chemotherapeutic resistance in hepatocellular carcinoma (HCC) is the use of effective chemosensitizers. We studied the complementary multi-targeted molecular mechanisms of metformin and celastrol in mice with diethylnitrosamine-induced HCC to investigate whether metformin could augment the sensitivity of HCC tissue to the effect of celastrol. Simultaneous administration of celastrol (2 mg/kg) and metformin (200 mg/kg) improved liver function, enhanced the histological picture and prolonged survival. Additionally, combination therapy exerted anti-inflammatory activity, as indicated by the decreased levels of TNF-alpha and IL-6. This protective role could be attributed to inhibition of inflammasome activation. Herein, our data revealed downregulated NLRP3 gene expression, suppressed caspase-1 activity and reduced levels of the active forms of IL-1 beta and IL-18. Under this condition, pyroptotic activity was suppressed. In contrast, in the celastrol and celastrol + metformin groups, the apoptotic potential was amplified, as revealed by the increase in the caspase-9 and caspase-3 levels and Bax:BCL-2 ratio. In addition to their repressive effect on the gene expression of NF kappa Bp65, TNFR and TLR4, metformin and celastrol inhibited phosphorylation-induced activation of I kappa B kappa B and NF kappa Bp65 and decreased I kappa B alpha degradation. Combination therapy with metformin and celastrol repressed markers of angiogenesis, metastasis and tumour proliferation, as revealed by the decreased hepatic levels of VEGF, MMP-2/9 and cyclin D1 mRNA, respectively. In conclusion, by inhibiting NLRP3 inflammasome and its prerequisite NF kappa B signalling, simultaneous administration of metformin and celastrol appears to have additive benefits in the treatment of HCC compared to cela monotherapy. This effect warrants further clinical investigation.
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