Nrf2-Mediated Antioxidant Response and Drug Efflux Transporters Upregulation as Possible Mechanisms of Resistance in Photodynamic Therapy of Cancers

Abstract

Photodynamic therapy (PDT) is a groundbreaking approach involving the induction of cytotoxic reactive oxygen species (ROS) within tumors through visible light activation of photosensitizers (PS) in the presence of molecular oxygen. This innovative therapy has demonstrated success in treating various cancers. While PDT proves highly effective in most solid tumors, there are indications that certain cancers exhibit resistance, and some initially responsive cancers may develop intrinsic or acquired resistance to PDT. The molecular mechanisms underlying this resistance are not fully understood. Recent evidence suggests that, akin to other traditional cancer treatments, the activation of survival pathways, such as the KEAP1/Nrf2 signaling pathway, is emerging as an important mechanism of post-PDT resistance in many cancers. This article explores the dual role of Nrf2, highlighting evidence linking aberrant Nrf2 expression to treatment resistance across a range of cancers. Additionally, it delves into the specific role of Nrf2 in the context of photodynamic therapy for cancers, emphasizing evidence that suggests Nrf2-mediated upregulation of antioxidant responses and induction of drug efflux transporters are potential mechanisms of resistance to PDT in diverse cancer types. Therefore, understanding the specific role(s) of Nrf2 in PDT resistance may pave the way for the development of more effective cancer treatments using PDT.

Keywords: Nrf2; antioxidant response; oxidative stress; photodynamic therapy; tumor resistance.

Figure 1

Photochemical generation of ROS during PDT. Upon absorption of light of appropriate wavelength by the PS, an electron is elevated to an excited singlet state (S₁) from the singlet ground state (S₀). This excited singlet state is transient and can release energy through photon emission (fluorescence). Alternatively, it may undergo intersystem crossing, leading to the formation of a long-lived excited triplet state (T₁). The T₁ state is responsible for generating reactive species, including O₂^•-, H₂O₂, HO^• and ¹O₂ through both type I and type II reactions.

Figure 2

Protein structure of (A) Nrf2 and (B) KEAP1 showing different domains.

Figure 3

Activation and response of Nrf2. Under normal condition, KEAP1 binds Nrf2 and package it for ubiquitination and proteosomal degradation with the help of Cullin 3-E3 ubiquitin ligase. In the presence of a stressor such as ROS and electrophiles, Nrf2 is activated and translocated into the nucleus where its binding to the antioxidant response element sequence leads to transcription of different cytoprotective genes.