Investigation of the protective effects of N-acetylcysteine and lycopene in an experimental hepatocellular carcinoma model induced by diethylnitrosamine

Aim: HCC is a multistep disease arising from the accumulation of genetic and epigenetic alterations. This process can be reproduced in experimental models using N-nitroso compounds, which may also cause environmental and endogenous exposure in humans and contribute to HCC development. Despite advances in HCC treatment, therapeutic resistance remains a major challenge, highlighting the need for novel strategies. Although lycopene and NAC have been reported to exert chemopreventive effects, the impact of their combined use on hepatocarcinogenesis has not yet been clarified. Therefore, this study aimed to investigate the effects of combined lycopene and NAC administration, known to support DNA repair mechanisms, on early-stage hepatocarcinogenesis in a DEN/TAA-induced HCC model using biochemical and histopathological analyses. Materials and Methods: Fifty-six mice were divided into five groups: Control, DEN, Lycopene+DEN, Lycopene+NAC+DEN, and NAC+DEN. Except for the Control group, HCC was induced by intraperitoneal DEN (weeks 3–10) and TAA (weeks 11–18). Lycopene and/or NAC were administered three days before DEN initiation and continued until week 24. Hepatic inflammatory (cytokines, Nrf2, NF-κB p65, p-NF-κB p65), apoptotic (Caspase-3, Caspase-9, Bax, Bcl-2), and neoplastic/fibrotic (GST-pi, Glypican-3, VEGF, MMP-2, TGF-β1) biomarkers were evaluated. Results: NAC didn't significantly alter NF-κB, VEGF, or MMP-2 levels. Lycopene reduced NF-κB but increased VEGF and MMP-2 expression. Lycopene and/or NAC exerted an antiapoptotic effect by decreasing the Bax/Bcl-2 ratio without Caspase-3 or Caspase-9 activation, and compared to DEN, increased TGF-β1, decreased glypican-3, and increased tumor nodules. Conclusion: Despite their recognized antioxidant, anti-inflammatory and anticancer properties, lycopene and NAC may paradoxically enhance carcinogenesis under certain conditions.