Mechanism of cordycepin enhancing doxorubicin against hepatocellular carcinoma in vitro and in vivo

Abstract

• Cordycepin combined with doxorubicin could significantly inhibit the activity, proliferation and migration of HepG-2 cells. • The combination of the two drugs can significantly inhibit the proliferation of transplanted HepG-2 in nude mice. • Based on the study of molecular mechanism of anti HCC by combination of drugs, MYC may be a potential target in the treatment of HCC. • Combination therapy for hepatocellular Carcinoma (HCC) is a multi-target and multi-pathway mechanism. Liver cancer is a serious disease with global impact. Due to the poor prognosis of liver cancer, there is an urgent need to develop new therapeutic options. The aim of the present study was to investigate the feasibility of cordycepin combined with doxorubicin for the treatment of liver cancer and its mechanism of action. In vitro and in vivo studies revealed that cordycepin combined with doxorubicin effectively inhibited cell proliferation and induced apoptosis in hepatocellular carcinoma. Network pharmacology analysis of the anticancer mechanism of cordycepin combined with doxorubicin showed that 82 potential targets were enriched in “Proteoglycans in cancer”, “TNF signaling pathway”, “MicroRNAs in cancer”, “Epithelial cell signaling in Helicobacter pylori infection”, “Pathways in cancer”. MYC is the target with the largest Degree value in the PPI network, revealing that MYC may play an important role in combination anticancer. It was further suggested that combined treatment could downstream of c-Myc to regulate apoptosis-related genes, such as BCL2 , MCL1 , PARP1 and CASP3 , thereby inducing apoptosis. At the same time, we demonstrated that the drug combination regulated the expression of genes related to cell migration, such as MMP9 , MMP3 and ICAM1 , thereby inhibiting cell migration. In vivo , the combined treatment suppressed the growth of HepG-2 xenograft-bearing nude mice by inducing apoptosis, and the inhibition rate of the combination group was higher than that of the single treatment group. In summary, the present study demonstrated that cordycepin potentiates the sensitivity of liver cancer cells to doxorubicin, suggesting that it may be a potential anticancer drug.