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Repurposing resveratrol for redox-mediated inhibition of MTH1 in breast cancer
Aaliya Taiyab1, Arunabh Choudhury1, Shaista Haider2
1Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India.
Abstract:
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 (Ka 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.
Insights
Resveratrol (RV) inhibits MTH1, an enzyme crucial for cancer cell survival. This inhibition increases reactive oxygen species (ROS), causing DNA damage and leading to breast cancer cell death, suggesting RV as a potential anti-cancer therapy.
Area of Science:
- Molecular Biology
- Cancer Research
- Biochemistry
Background:
- Cancer cells exhibit increased metabolic activity, leading to higher reactive oxygen species (ROS) levels and DNA damage.
- Mutant form of 8-oxoguanine glycosylase 1 (MTH1) is essential for cancer cell survival by sanitizing oxidized nucleotide pools.
- MTH1 inhibition causes DNA damage and cell death in cancer cells.
Purpose of the Study:
- To investigate resveratrol (RV) as a potential inhibitor of MTH1.
- To evaluate the anti-cancer effects of RV on breast cancer cells.
Main Methods:
- Molecular docking and MD simulations to assess RV binding to MTH1.
- Fluorescence binding studies to determine binding affinity and inhibition constants.
- Cell proliferation assays and apoptosis studies on MCF-7 breast cancer cells.
Main Results:
- Resveratrol demonstrated effective binding to the MTH1 active site, forming a stable complex.
- RV exhibited high binding affinity (Ka 6.2 × 105M-1) and inhibited MTH1 activity (IC50 18.13 µM).
- RV significantly inhibited MCF-7 cell proliferation, induced apoptosis, increased ROS production, and caused oxidative stress.
Conclusions:
- Resveratrol acts as an MTH1 inhibitor, disrupting DNA repair mechanisms in cancer cells.
- RV's ability to induce oxidative stress and cell death supports its potential as an anti-cancer therapeutic agent.
- Further evaluation of RV as an MTH1 inhibitor for breast cancer treatment is warranted.
