Summary of redox-targeted therapeutic strategies in cancer.
| Strategy | Key agents | Mechanism of action | Cancer types | Clinical status | Advantages | References |
|---|---|---|---|---|---|---|
| Pro-oxidant therapy | Doxorubicin, arsenic trioxide (ATO), β-lapachone, elesclomol | Redox cycling; superoxide via mitochondrial ETC disruption; exceeds cytotoxic ROS threshold. | Leukaemia, APL, solid tumours | Approved/Phase I–III | Selective cancer cell killing due to elevated basal ROS | [120] |
| GSH synthesis inhibition | Buthionine sulfoximine (BSO), erastin, imuthiol | Inhibits γ-GCS; depletes GSH; erastin blocks system Xc– causing GPX4-mediated ferroptosis. | Melanoma, ovarian, neuroblastoma, glioblastoma | Phase I–II | Sensitises drug-resistant tumours; induces ferroptosis | [132, 133] |
| Thioredoxin system inhibition | Auranofin (TrxR inhibitor), PX-12, PMX464 | Covalent TrxR selenocysteine modification; impairs peroxiredoxin recycling; elevates ROS. | Lung, ovarian, colorectal cancer | Phase I–II | Well-tolerated; repurposed gold-based drug | [133, 134] |
| Nrf2 pathway suppression | ML385, brusatol, trigonelline, halofuginone | Blocks Nrf2-Keap1 axis; reduces NQO1, HO-1, GPx; sensitizes to oxidative damage. | Lung, pancreatic, liver, breast cancer | Preclinical/Phase I | Overcomes chemo-resistance; broad spectrum | [131, 132] |
| Radiotherapy and ROS modulation | Ionising radiation ± nimorazole, ATO | Hydroxyl radicals via water radiolysis; ROS amplifiers enhance DNA DSB formation. | Head & neck, brain, breast, prostate | Standard of care and trials | Well-established; synergistic with antioxidant inhibition | [99, 143] |
| Photodynamic therapy (PDT) | Photofrin, talaporfin, 5-ALA, temoporfin | Photosensitizer + light → singlet oxygen (1O2); oxidizes lipids, proteins, nucleic acids. | Skin, oesophageal, lung, bladder, H&N | Approved/Phase II–III | Tumour-localised; minimal systemic toxicity | [144, 145] |
| ROS + immunotherapy combination | Anti-PD-1/PD-L1 + pro-oxidant agents | Induces ICD; releases DAMPs (CRT, HMGB1, ATP); activates DCs; enhances checkpoint blockade. | Melanoma, NSCLC, colorectal, bladder | Phase I–III | Converts ‘cold’ to ‘hot’ tumours; broadens IO response | [134, 144] |
| Nanoparticle-based CDT | Iron oxide NPs, Cu-MOFs, GOx nanoplatforms, TiO2-NPs | Fenton/Fenton-like reactions; tumor microenvironment H2O2 amplification; chemodynamic therapy. | Liver, breast, glioma, lung cancer | Preclinical/Phase I | Spatially controlled ROS; reduced systemic toxicity | [134, 149] |
| Ferroptosis induction | Erastin, RSL3, sulfasalazine, FIN56 | Inhibits system Xc– or GPX4; promotes iron-dependent lipid peroxidation and lethal lipid ROS accumulation. | Pancreatic, lung, liver, glioblastoma, therapy-resistant tumors | Preclinical/early phase | Targets redox-adapted and drug-resistant cancer cells; synergistic with chemotherapy and immunotherapy | [156, 157] |
| ROS-responsive drug delivery and prodrugs | Thioketal nanoparticles, boronic ester prodrugs, ROS-responsive polymers | ROS-triggered drug release selectively within oxidative tumor microenvironments. | Solid tumors, hypoxic tumors | Preclinical/early phase | Reduced systemic toxicity; enhanced tumor specificity | [34, 134, 149] |
TU: Conceptualization, Supervision. TK: Resources, Writing—review & editing. AA: Formal analysis. MT: Investigation. TS: Project administration, Validation. NPA: Supervision, Writing—original draft. MH: Formal analysis, Resources. AZ: Supervision, Data curation. ATA: Writing—original draft. AKJ: Writing—review & editing. NA: Investigation, Supervision. NJ: Supervision. RSN: Writing—review & editing, Resources. S Sharma: Investigation, Writing—review & editing. MMM: Conceptualization, Writing—review & editing. MTH: Project administration, Validation. S Saha: Investigation. All authors read and approved the submitted version.
The authors declare that they have no conflicts of interest.
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