Suppression of colorectal cancer growth: Interplay between curcumin and metformin through <scp>DMT1</scp> downregulation and <scp>ROS</scp> ‐mediated pathways

The rising incidence of colorectal cancer (CRC) poses significant healthcare challenges. This study explored the therapeutic potential of combined curcumin (CUR) and metformin (MET) treatment in CRC models. Our findings indicate that the combination treatment (COMB) effectively downregulates the expression of divalent metal transporter-1 (DMT-1), leading to a reduction in cell proliferation aligned with suppression of the pAKT/mTOR/Cyclin D1 signaling pathway. The COMB increased reactive oxygen species (ROS) production, triggering activation of the NRF2/KEAP1 pathway. This pathway elicits an antioxidant response to manage oxidative stress in CRC cell lines. Interestingly, the response of NRF2 varied between CT26 and HCT116 cells. Moreover, our study highlights the induction of apoptosis and autophagy, as evidenced by upregulations in Bax/Bcl-2 ratios and autophagy-related protein expressions. Notably, the COMB promoted lipid peroxidation and downregulated xCT levels, suggesting the induction of ferroptosis. Ferroptosis has been shown to activate autophagy, which helps eliminate cells potentially damaged by the increased oxidative stress. Furthermore, the COMB effectively diminished the migratory ability of CRC cells. In vivo experiments using CRC-bearing mouse models, the results confirmed the anti-tumor efficacy of the COMB, leading to substantial inhibition of tumor growth without inducing general toxicity. In conclusion, our study suggests that combining CUR with MET holds promise as a potential option for CRC treatment, with critical mechanisms likely involving ROS elevation, autophagy, and ferroptosis.