Combining Sorafenib, Se-methylselenocysteine, and α-Ketoacid for synergistic cytotoxicity in Hepatocellular carcinoma cell lines

Hepatocellular carcinoma (HCC) remains a major global health challenge, particularly in advanced stages where treatments options are limited. Sorafenib, the standard systemic therapy for advanced HCC, offers only modest survival benefits, and is frequently associated with resistance and adverse effects, highlighting the need for improved therapeutic strategies. Se-methylselenocysteine (MSC), a redox-active selenium compound, has demonstrated selective cytotoxicity in cancer cells, particularly when combined with α-ketoacid (Indole-3-pyruvic acid (IPA) and α-Keto-γ-methylthiobutyric acid sodium salt (KMB)). This study evaluated the therapeutic potential of MSC in combination with sorafenib and/or α-ketoacid in HCC cell lines (HEPG2 and Huh7). Our findings indicate that MSC combined with sorafenib significantly decreased cell viability in Huh7 cells but had a less pronounced effect in HEPG2 cells compared to sorafenib alone. In contrast, triple combinations of MSC, sorafenib, and α-ketoacid markedly enhanced antiproliferative effects in both cell lines. Specifically, the MSC-IPA-sorafenib combination demonstrated greater efficacy in reducing sorafenib's IC50 values than MSC-KMB-sorafenib. At the molecular level, sorafenib exhibited district effect on key signaling pathways: in Huh7 cells, it suppressed the MAPK/ERK and AKT/mTOR pathways, whereas in HEPG2 cells, it increased p-ERK, p-mTOR, and p-S6 expression, suggesting a cell-context-dependent response. Importantly, both triple combinations (sorafenib-MSC-IPA and sorafenib-MSC-KMB) robustly inhibited the AKT/mTOR pathway in both cell lines, achieving greater suppression than sorafenib monotherapy. These results highlight the potential of combining MSC, sorafenib, and α-ketoacid as a promising strategy to enhance HCC treatment efficacy. Further in vivo studies are warranted to confirm their therapeutic potential in HCC.