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

Figures & data

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.

Abbreviations: H₂O₂, hydrogen peroxide; HO^•, hydroxyl radical; ONOO^•, peroxynitrite radical; ¹O₂, singlet oxygen; O₂^•-, superoxide radical; R, alkyl radical, ROO, peroxy radical; S₀, singlet ground state; S₁, excited singlet state; T₁, excited triplet state.

Figure 2 Protein structure of (A) Nrf2 and (B) KEAP1 showing different domains.

Abbreviations: BTB, broad-Complex/TramTrack/Bric-a-Brac domain; bZIP, basic region-leucine zipper; CBP, CREB-binding protein; CHD6, chromodomain helicase DNA-binding protein 6; CNC, cap ‘n’ collar; CUL 3, Cullin 3; DPP3, dipeptidyl peptidase 3; GR, glucocorticoid receptor; HRD1, 3-hydroxy-3-methylglutaryl reductase 1; IVR, intervening region; KEAP1, Kelch-like ECH-associated protein 1; Neh, Nrf2-ECH homology domain; Nrf2, Nuclear factor (erythroid-derived 2)-like 2; RNS, reactive nitrogen species; ROS, reactive oxygen species; RXRα, retinoid X receptor-alpha; sMaf, small musculo-aponeurotic fibrosarcoma protein; SRC3, steroid receptor co-activator 3; UbcM2, ubiquitin conjugating enzyme; β-TrCP, β-transducin repeat-containing protein.

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.

Abbreviations: ARE, antioxidant response element; CUL 3, Cullin 3-E3 ubiquitin ligase; Keap1, Kelch-like ECH-associated protein 1; Nrf2, Nuclear factor (erythroid-derived 2)-like 2; sMaf, small musculo-aponeurotic fibrosarcoma protein.