Ginsenoside Rg3 and sorafenib combination therapy relieves the hepatocellular carcinomaprogression through regulating the HK2-mediated glycolysis and PI3K/Akt signaling pathway

Abstract

Hepatocellular carcinoma (HCC) is the most common pathological type of primary hepatic carcinoma. This study investigated the effects of ginsenoside Rg3 (Rg3) and sorafenib (SFN) combination therapy on HCC progression. The HCC-related data were obtained from TCGA database, and the data of HK2 mRNA, clinicopathological features, and survival outcomes were extracted using R Programming 4.0. The human hepatoma cell lines HepG2 and Bel7404 were used. Cell viability was tested using the MTT assay. Glucose consumption and lactate levels of HCC cells were detected using the corresponding kits. Western blotting was used to determine the protein expression of HK2, PI3K, and Akt. HK2 was overexpressed in patients with HCC. Compared with patients with overexpressed HK2, those with low levels of HK2 achieved a longer survival time. In addition, the Rg3 and SFN combination therapy significantly reduced cell viability, glucose consumption, lactate levels, and protein expression of HK2, PI3K, and Akt in HCC cells. Additionally, the Rg3 and SFN combination therapy exhibited a better effect than the single drug group. Inhibition of the PI3K/Akt signaling pathway or exogenous lactate intervention reversed the effects of Rg3 and SFN combination therapy in HCC cells. In conclusion, Rg3 has a synergistic effect on the sensitivity of HepG2 and Bel7404 hepatoma cells to SFN, which is related to HK2-mediated glycolysis and the PI3K/Akt signaling pathway.

A pan-cancer analysis of the role of hexokinase II (HK2) in human tumors

“…Recently, a fifth hexokinase, hexokinase domain containing 1 (HKDC1), was shown to have significant overexpression in liver cancer compared to healthy liver tissue 26 . Studies revealed that inhibiting HK2-mediated glycolysis can enhance the anti-hepatocellular carcinoma activity of sorafenib 27 , 28 . HK2 may be a possible therapeutic target for liver cancer.…”

Metformin Enhances the Anti-Cancer Efficacy of Sorafenib via Suppressing MAPK/ERK/Stat3 Axis in Hepatocellular Carcinoma

“…PI3K/mTOR inhibitor GSK1059615 and sorafenib-loaded PLGA-PEG-mal deblock copolymer proved efficacious in activating NF-kB, inhibiting programmed cell death ligand 1 (PD-L1), and ameliorating sorafenib resistance [ 48 ]. In addition to targeted inhibition of signaling pathways to increase sorafenib efficacy, combining a natural product, such as ginsenoside Rg3, with sorafenib also showed enhanced inhibition of HCC cells [ 49 ]. Several efforts are underway to improve HCC therapy using immune checkpoint inhibitors as single agents and in combination.…”

Unveiling the experimental proof of the anticancer potential of ginsenoside Rg3 (Review)

“…Additionally, GS-Rg3 combined with artemisinin can inhibit STAT3 signal transduction in hepatocellular carcinoma cancer cells, synergistically reduce the viability of cells, induce apoptosis and inhibit the growth of mouse hepatocellular carcinoma ( 48 ). Similarly, the combined therapy of GS-Rg3 and sorafenib can mitigate the progression of hepatocellular carcinoma by inhibiting hexokinase 2-mediated glycolysis and the PI3K/Akt signaling pathway ( 49 ). Moreover, a meta-analysis has demonstrated that transarterial chemoembolization combined with GS-Rg3 can effectively enhance the objective response rate and disease control rate of hepatocellular carcinoma while reducing adverse reactions to treatment ( 50 ).…”