Cell Death Pathways in Photodynamic Therapy of Cancer

Abstract

Photodynamic therapy (PDT) is an emerging cancer therapy that uses the combination of non-toxic dyes or photosensitizers (PS) and harmless visible light to produce reactive oxygen species and destroy tumors. The PS can be localized in various organelles such as mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and plasma membranes and this sub-cellular location governs much of the signaling that occurs after PDT. There is an acute stress response that leads to changes in calcium and lipid metabolism and causes the production of cytokines and stress response mediators. Enzymes (particularly protein kinases) are activated and transcription factors are expressed. Many of the cellular responses center on mitochondria and frequently lead to induction of apoptosis by the mitochondrial pathway involving caspase activation and release of cytochrome c. Certain specific proteins (such as Bcl-2) are damaged by PDT-induced oxidation thereby increasing apoptosis, and a build-up of oxidized proteins leads to an ER-stress response that may be increased by proteasome inhibition. Autophagy plays a role in either inhibiting or enhancing cell death after PDT.

New Approaches to Photodynamic Therapy from Types I, II and III to Type IV Using One or More Photons

“…Since there are several processes involved in causing PDT induced cell killing it is not surprising that any of the three commonly known cell death mechanisms, namely apoptosis, necrosis or autophagy can be triggered [5,10,23,26,54]. Confocal microscopy and Förster Resonance Energy Transfer (FRET) imaging on cultured cells demonstrated that common PDT PSs are found to localize in different subcellular structures such as the plasma membrane (Photofrin®), mitochondria (phthalocyanine Pc4), lysosomes, nucleus, endoplasmic reticulum or the Golgi apparatus [5,23,26,43,55].…”

“…Type III PSs are usually Antioxidant Carrier Sensitizers (ACS), also called Modified Type I (MTO) PSs, which combine properties leading to the efficient generation of singlet oxygen and decreasing the concentration of native free radicals in malignant cells. ACS are usually synthesized from the molecular backbone of originally active PSs used in clinical PDT, such as substituted porphyrin derivatives [5,10,15,17,19,24,26,28,29,[40][41][42][43][44]. Currently novel types of pro-drugs such as combretastatins, discussed fully in section 4.4, are emerging which can be directly photo- activated by multiphoton excitation without the need for the presence of oxygen within the target tissue (see the section on Alternative Strategy for Two-photon Phototherapy (2P-PDT) without ROS below).…”

Efeito da proteína p53 nas respostas celulares à terapia fotodinâmica com 1,9-dimetil azul de metileno

“…O tipo de morte celular desencadeado pela TFD irá depender de vários fatores, entre eles: as características químicas do fotossensibilizador, sua concentração e o tempo de incubação com o mesmo, a dose de luz e o tipo celular (Mroz et al, 2011).…”

“…Elevadas doses de luz ou altas concentrações de fotossensibilizador tendem a causar a morte celular por necrose (Mroz et al, 2011). As características morfológicas da morte por necrose compreendem o aumento do volume celular, a vacuolização do citoplasma e o rompimento da membrana plasmática (Edinger e Thompson, 2004).…”

“…Um terceiro tipo de morte induzida pela TFD é a morte celular relacionada à autofagia (Mroz et al, 2011). Também é conhecida como morte celular autofágica, cujo termo foi criado baseado na característica morfológica de extensa vacuolização do citoplasma de células em processo de morte.…”