Pharmacological targeting of nuclear factor (erythroid-derived 2)-like 2 (NRF2): a potential strategy to improve the efficacy of oncological photodynamic therapy

The recalcitrance of tumors to photodynamic therapy (PDT) has been linked to PDT-induced activation of survival pathways in sublethally afflicted cancer cells that modulate cellular responses to oxidative stress and damage. Survival signaling manifests in regions of the tumor where the tumor cells are insufficiently photosensitized or subjected to inadequate fluence rates. The survival signaling in these tumor regions is believed to account for tumor recurrence. Accordingly, PDT efficacy can be improved by intervening in these pathways using molecular inhibitors of key modulators of survival signaling, thereby reducing the number of sublethality afflicted cancer cells whilst increasing therapeutic efficacy. A promising target for pharmacological intervention is the nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway, which induces the antioxidant and xenobiotic stress response that helps cells cope with prolonged periods of hyperoxidative stress after PDT. This review outlines our current understanding of this pathway, how it is activated, and how it confers cytoprotective effects and ensures cell survival. Additional distinguishing features of the review are that (1) studies are addressed in which PDT activation of the NRF2 pathway has been demonstrated; (2) an exhaustive overview of NRF2 pathway inhibitors is presented that could serve as potential adjuvants in PDT regimens to augment therapeutic efficacy in treatment-resistant tumors and cancers that recur after PDT; (3) molecular docking analyses are included that show potential interactions between the NRF2 inhibitors and the redox sensor KEAP1; and (4) an elaborate account is provided on the potential bottlenecks and caveats that can be encountered when using NRF2 inhibitors in the development of fourth-generation photosensitizers for oncological PDT.