Mechanism Of Rhizoma Paridis Saponins And Curcumin Improving The Effect Of Sorafenib On Liver Cancer

Hepatocellular carcinoma(HCC)was the third leading cause of cancer death worldwide.Sorafenib,as a multi-kinase inhibitor,was the first FDA-approved anti-hepatocellular carcinoma drug.However,about 70%sorafenib-treated patients showed drug resistance after six months and the resistance mechanism was related to glycolipid metabolism and tumor inflammatory microenvironment.Rhizoma Paridis saponins(RPS)and curcumin as natural products have shown multiple antitumor activity through regulating glycolipid metabolism and inflammation and so forth.In this research,we tried to verify the probability of combinatorial treatment of RPS and sorafenib and valued the mechanism of combinatorial treatment of sorafenib and curcumin by using H22 mice model and metabolomics and molecular biology methods.As a result,RPS increased the antitumor effect of sorafenib in H22 mice.They decreased levels of AST and ALT in serum,and AFP and MDA in liver tissues,which indicated their liver protective activity.They also up-regulated the activity of NOX and SDH,concentration of ATP,and down-regulated the mRNA and protein levels of HIF-la and concentration of lactate,which suggested they protected against mitochondria damage and inhibited anaerobic glycolysis.Meanwhile,the combination group remarkably down-regulated the concentration of octadecanoic acid and hexadecanoic acid in serum,and tetradecanoic acid in liver tissues compared with model group(*p<0.05).Relative regulation mechanism included their decreasing mRNA levels of FASN,CPT1,GLUT1,LDHA,AKT,and mTOR,increasing the protein expression of p53 in tumor and liver tissues(*p<0.05)and decreasing protein levels of p-PI3K and p-mTOR in liver tissues and FASN in serum.Furthermore,curcumin increased the anticancer effects in sorafenib-treated H22 mice and protected liver function through reducing levels of ALT and AFP,activating immune function by increasing T cells and NK cells in vivo.Besides,combinatorial treatment inhibited epithelial-to-mesenchymal transition(EMT)through regulating hypoxia,inflammation and PI3K/AKT/mTOR pathway and regulated the disorder of glycolipid metabolism.Furthermore,docking study proved the strong affinity between curcumin and protein of STAT3,a key lipid metabolism enzyme FASN and AKT.These experiments provided evidences for the addition of curcumin in diet enhancing the antitumor efficacy of sorafenib through activating immune function,down-regulating EMT and reversing the disorder of metabolism.All of that provided possibility to increased the antitumor effect of sorafenib by drug compatibility of RPS through protection against mitochondria damage,inhibition of anaerobic glycolysis and suppression of lipid synthesis based on PI3K/AKT/mTOR pathway.This study also proved more evidences for the mechanism of co-treatment of curcumin enhanced the effect of sorafenib through activating immune function,down-regulating EMT and regulating the disorder of metabolism.It is valuable to investigate the anti-liver cancer efficacy of the.three drugs of RPS,curcumin and sorafenib.All in all,this study provided new experimental gist for overcoming sorafenib resistance and had great significance to further development of combinatorial treatment to enhance the efficacy of anti-hepatocellular carcinoma.