| Abstrakt: |
Photodynamic therapy (PDT) is a novel treatment for cancer and certain non-malignant conditions, which employs a photosensitive drug followed by light in the visible range to produce an oxidative stress and cell death in the targeted tissue. The photosensitizers (PSs) are most commonly porphyrins or related hydrophobic macrocycles that localize in one or more intracellular membranes and that are activated by long-wavelength (red) visible light. Singlet molecular oxygen and other reactive oxygen species are the primary damaging species produced by PDT, and these oxidize cellular substrates, including lipids and proteins of the membranes in which the PS resides. PDT is an efficient inducer of apoptosis; this has been demonstrated in many cell types and with many different PSs. Once induced, apoptosis follows recognized paths but most commonly the intrinsic (mitochondrial) pathway, mediated by activated caspases and resulting in DNA fragmentation and morphological apoptosis. The aspects of apoptosis that are unique to PDT are the molecular targets, the types of initial cellular damage, and the immediate consequences of that damage. Many PSs target mitochondria, resulting in changes in the permeability transition pore complex, the apoptotic proteins Bcl-2 and Bcl-xL, and/or phospholipids, especially cardiolipin. Some PSs also target the endoplasmic reticulum (ER), damaging calcium pumps and resulting in the efflux of stored calcium into the cytosol and subsequently mitochondria. With PSs that localize in lysosomes, photoactivation damages the lysosomal membrane, causing release of cathepsins and other factors that can activate apoptosis mediators such as Bid that in turn promote mitochondrial apoptosis. Although the plasma membrane is not commonly a direct target of most PSs, it can be secondarily affected by the release of ligands of membrane receptors, such as Fas ligand. Evidence supporting the roles of each of the organelles in PDT-induced apoptosis are reviewed, and a model is proposed in which mitochondrial damage by PDT directly activates apoptosis and damage to the ER and/or the lysosome promotes the central mitochondrial pathway of apoptosis. [ABSTRACT FROM AUTHOR] |
