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Hepatocellular carcinoma (HCC) treatment is a major challenge. Although andrographolide (Andro) has an anti-proliferation effect on HCC, its underlying mechanism is not yet elucidated, and whether Andro can inhibit HCC metastasis has not been reported. The present study aimed to clarify whether Andro inhibits SK-Hep-1 cell proliferation and HCC metastasis, and the mechanisms. The results showed that Andro significantly reduced the survival of HCC cells and tumor weight and volume in tumor-bearing nude mice. Andro also triggered apoptosis of HCC cells and upregulated MIR22HG, Cleaved Caspase 9/7/3 expression levels, and downregulated BCL-2 mRNA, BCL-2 expression levels. Knockdown of MIR22HG or overexpression of HuR attenuated the effects of Andro on the signal transduction of mitochondrial apoptotic pathway and proliferation ability in HCC cells. Moreover, Andro significantly reduced the invasive ability of the cells and the level of HCC cell lung metastasis, upregulated miR-22-3p expression level and downregulated HMGB1 and MMP-9 expression levels. MIR22HG or miR-22-3p knockdown attenuated the effects of Andro on the signaling of HMGB1/MMP-9 pathway and invasive ability in HCC cells, while the overexpression of HMGB1 attenuated the inhibitory effects of Andro on the MMP-9 expression level and invasive ability in HCC cells. Thus, the regulation of MIR22HG-HuR/BCL-2 and MIR22HG/HMGB1 signaling pathways is involved in the anti-HCC proliferation and metastasis effects of Andro. This study provided a new pharmacological basis for Andro in HCC treatment and, for the first time, identified a natural product molecule capable of positively regulating MIR22HG, which has a robust biological function., (© 2023. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Sorafenib, an oral multiple kinase inhibitor, is the standardized treatment for hepatocellular carcinoma (HCC). One strategy to improve HCC therapy is to combine agents that target key signaling pathways. In this study we set out to investigate the effect of combining sorafenib with either bevacizumab (anti-VEGF), panitumumab (anti-EGFR) or ramucirumab (anti-VEGFR2) on HepG2 cancer cell line with the aim of improving efficacy and possibility of therapeutic dose reduction of sorafenib.: HepG2 cancer cell line was treated with sorafenib alone or in combination with either bevacizumab, panitumumab or ramucirumab. Cell proliferation; apoptosis and cell cycle distribution; gene expression of VEGFR2, EGFR, MMP-9 and CASPASE3; the protein levels of pVEGFR2 and pSTAT3 and the protein expression of CASPASE3, EGFR and VEGFR2 were determined. Combined treatments of sorafenib with ramucirumab or panitumumab resulted in a significant decrease in sorafenib IC 50 . Sorafenib combination with ramucirumab or bevacizumab resulted in a significant arrest in pre-G and G0/G1 cell cycle phases, significantly induced apoptosis and increased the relative expression of CASPASE3 and decreased the anti-proliferative and angiogenesis markers´ MMP-9 and pVEGFR2 or VEGFR2 in HepG2 cells. A significant decrease in the levels of pSTAT3 was only detected in case of sorafenib-ramucirumab combination. The combined treatment of sorafenib with panitumumab induced a significant arrest in pre-G and G2/M cell cycle phases and significantly decreased the relative expression of EGFR and MMP-9. Sorafenib-ramucirumab combination showed enhanced apoptosis, inhibited proliferation and angiogenesis in HepG2 cancer cells. Our findings suggest that ramucirumab can be a useful as an adjunct therapy for improvement of sorafenib efficacy in suppression of HCC., (© 2022. The Author(s).)