Mechanisms in photodynamic therapy: part two—cellular signaling, cell metabolism and modes of cell death

Abstract

Photodynamic therapy (PDT) has been known for over a hundred years, but is only now becoming widely used. Originally developed as a tumor therapy, some of its most successful applications are for non-malignant disease. In the second of a series of three reviews, we will discuss the mechanisms that operate in PDT on a cellular level. In Part I [Castano AP, Demidova TN, Hamblin MR. Mechanism in photodynamic therapy: part one-photosensitizers, photochemistry and cellular localization. Photodiagn Photodyn Ther 2004;1:279-93] it was shown that one of the most important factors governing the outcome of PDT, is how the photosensitizer (PS) interacts with cells in the target tissue or tumor, and the key aspect of this interaction is the subcellular localization of the PS. PS can localize in mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and plasma membranes. An explosion of investigation and explorations in the field of cell biology have elucidated many of the pathways that mammalian cells undergo when PS are delivered in tissue culture and subsequently illuminated. There is an acute stress response leading to changes in calcium and lipid metabolism and production of cytokines and stress proteins. Enzymes particularly, protein kinases, are activated and transcription factors are expressed. Many of the cellular responses are centered on mitochondria. These effects frequently lead to induction of apoptosis either by the mitochondrial pathway involving caspases and release of cytochrome c, or by pathways involving ceramide or death receptors. However, under certain circumstances cells subjected to PDT die by necrosis. Although there have been many reports of DNA damage caused by PDT, this is not thought to be an important cell-death pathway. This mechanistic research is expected to lead to optimization of PDT as a tumor treatment, and to rational selection of combination therapies that include PDT as a component.

Acumulación celular y el efecto de anti-Leishmania de protoporfirina IX exógena y endógena después del tratamiento fotodinámico

“…Cellular localization is an important issue, since it is related with the mechanism of cell death trigger. Photosensitizers localized within mitochondria are mostly associated with the apoptotic (some autophagic) death mechanism involved, i.e., caspase (or caspase-independent) activation and mitochondrial dysfunction (potential disruption of mitochondrial membrane and cytochrome C release) giving rise to morphological changes: bleeding, chromatin condensation and alteration of cell adhesion molecules (29)(30)(31)(32)(33)(34). Confocal images show overlapping of PpIX red fluorescence and MitoTracker Green fluorescence which strongly suggest PpIX mitochondrial localization in infected and non-infected THP-1 cells.…”

Photodynamic therapy with 5‐aminolevulinic acid and diamino acid derivatives of protoporphyrin IX reduces papillomas in mice without eliminating transformation into squamous cell carcinoma of the skin

“…Until now, carcinoma induction after PDT of normal skin has not been noticed. 51 However, because of the latent period in cancer development, long-term follow up is desired 5,6 even though PDT may confer advantages over conventional treatment of cancer.…”

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].…”

“…This may not only induce secondary necrosis, but also lead to the overexpression of vascular endothelial growth factor (VEGF) to make up for the loss of blood vessels. Hence the combination of PDT with antiangiogenic agents has been suggested to improve PDT treatment outcomes [5,23,26,54].…”