Synergistic antitumor effect of naproxen and sorafenib in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most prevalent and deadliest cancer types in the world. Due to the inevitable development of resistance to classical chemotherapy and current targeted therapies, combination therapy became an important strategy. Recently drug repurposing studies have emphasized the potential of non-steroidal anti-inflammatory drugs (NSAIDs) in exhibiting anti-tumor activities in different cancer types, including HCC. In this study, we explored the synergistic bioactivity of naproxen in combination with sorafenib in HCC cell lines. Network reconstruction analysis, performed to identify key factors mediating the synergistic therapeutic effects of sorafenib and naproxen revealed apoptosis pathways enriched in both sorafenib and naproxen networks. CAPN2 emerged as the common gene shared between the two networks. In vitro studies on Huh7 and Mahlavu cells revealed that induction of apoptosis was associated mainly with the PI3K/AKT pathway inhibition. Furthermore, combined treatment of naproxen and sorafenib led to the downregulation of CAPN2 expression, suggesting a potential link to apoptosis and PI3K/AKT pathway regulation, which needs further investigation. In conclusion, combining sorafenib with naproxen presents a promising strategy with potential synergistic therapeutic benefits in HCC. ### Competing Interest Statement The authors have declared no competing interest.