Overview of Cell Death Mechanisms Induced by Rose Bengal Acetate-Photodynamic Therapy

Figure 3

RBAc-PDT-mediated photocytotoxicity in HeLa tumour cells. RBAc (Rose Bengal Acetate) crosses the plasma membrane localizing in perinuclear region. Cytoplasmic esterases remove acetate groups and restore photoactive Rose Bengal molecules, producing ROS when excited by visible green light at 530 ± 15 nm (Total dose 1.6 J/cm²). RBAc treatment induces cell death in HeLa cells by apoptosis and autophagy in a time-related manner. The onset of apoptosis is sustained by four different pathways. (1) Mitochondrial or intrinsic pathway: Caspase 9 is the first activated caspase (2–8 h after irradiation). Cytosolic Bax monomers translocate to the OMM (Outer Mitochondrial Membrane), Δ𝜓m (mitochondrial transmembrane potential) collapses and cytochrome c is released into the cytosol through pores formed by Bax oligomers, Bax-associated PTPC (Permeability Transition Pore Complex), Bax-mediated lipid bilayer destabilization, and Bax-tBid association. (2) Extrinsic pathway: ROS-mediated trimerization of death receptors (such as TNF-α) activates caspase 8 (8–12 h after irradiation). (3) ER stress-mediated pathway: ER (Endoplasmic Reticulum) stress, marked by Grp78 (glucose-regulated protein 78) upregulation and eIF2α (eukaryotic Initiation Factor 2 alpha) phosphorilation, early (1 h) after irradiation, mediates [Ca²⁺]_𝑖 increment at 12 h and caspase 12 cleavage at 18 h after irradiation. (4) Caspase-independent pathway: release of apoptogenic factors from mitochondria, following Δ𝜓m drop, triggers chromatin fragmentation without caspase 3 involvement. Autophagic cell death occurs at 8 h after irradiation.