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TrxR Inhibition and Nrf2-FOXO3 Modulation by Repurposed Drugs: A Redox Strategy to Reverse Cancer Multidrug
Charan Singh Pawar1, Nagarajan Rajendra Prasad1
1Department of Biochemistry and Biotechnology, Annamalai University, Chidambaram, Tamil Nadu, India.
Drug Development Research
|July 30, 2026
Summary
Redox-based drug repurposing combats multidrug-resistant (MDR) cancer by re-sensitizing tumors to chemotherapy. Targeting imbalanced redox signaling with repurposed drugs like metformin and auranofin shows promise for improved cancer treatment outcomes.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Multidrug-resistant (MDR) cancer is often driven by imbalanced redox signaling, which impairs chemotherapy efficacy and promotes cancer cell survival.
- Key mechanisms in MDR include thioredoxin reductase (TrxR) amplification and Keap1-Nrf2-FOXO3 pathway activation, leading to increased drug efflux and antioxidant defenses.
Purpose of the Study:
- To explore redox-based drug repurposing as a strategy to overcome MDR in cancer.
- To investigate the potential of repurposed drugs to restore chemosensitivity by targeting redox signaling pathways.
Main Methods:
- Review of preclinical studies on repurposed drugs (metformin, auranofin, brusatol, natural polyphenols) that modulate redox signaling.
- Examination of nanotechnology advancements, combination therapies (with anticancer drugs, ferroptosis inducers), and redox-responsive delivery systems.
- Focus on biomarker-driven patient classification based on TrxR expression or Keap1/Nrf2 mutations.
Main Results:
- Repurposed drugs increase reactive oxygen species (ROS), enhancing MDR cell sensitivity to chemotherapy by inhibiting Nrf2 or TrxR.
- Nanotechnology and combination therapies improve tumor selectivity and reduce systemic toxicity.
- Preclinical data demonstrate suppression of antioxidant pathways, inhibition of efflux pumps, and effective redox-responsive drug delivery.
Conclusions:
- Redox-targeted drug repurposing is a viable precision strategy for overcoming MDR cancer and restoring chemosensitivity.
- Future directions include advanced delivery systems, adaptive clinical trials, and specific redox profiling for clinical translation.
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