Repurposing resveratrol for redox-mediated inhibition of MTH1 in breast cancer

The increased metabolic activity in cancer cells often leads to higher levels of reactive oxygen species compared to normal cells, which can cause damage to cellular components, including DNA. Cancer cells rely on MTH1 to maintain their DNA integrity and cellular function to counteract this damage. MTH1 is critical in sanitizing oxidized nucleotide pools by removing damaged nucleotides. Inhibition of MTH1 disrupts this repair process, leading to increased DNA damage and cell death in cancer cells. In this study, we present resveratrol (RV) as a potential MTH1 inhibitor. Docking and MD Simulations illustrated the effective binding of RV to the active site of the MTH1 protein, forming a notably stable complex. The fluorescence binding studies estimated a high binding affinity of RV with MTH1 (K_a 6.2 × 10⁵M^-1, inhibiting MTH1 activity with IC₅₀ 18.13 ± 1.08 µM. The inhibitory effects of RV on the proliferation of breast cancer cells (MCF-7) revealed significant inhibition in cell growth, leading to apoptosis. RV significantly increases ROS production, inducing considerable oxidative stress and ultimately resulting in cell death. Our study offers a rationale for evaluating RV as an MTH1 inhibitor for potential anti-cancer therapy, particularly in breast cancer.