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The role of phagocytosis in cell deaths by photodynamic therapy
No full textResistance to cell death and the ability to overrule immunosurveillance represent two hallmarks of tumour cells. The optimal cancer treatment should combine the induction of cell death and immunostimulatory effects based on immune cells activation consequent to the immunogenic characteristics of dead cells and their removal. The dynamic interplay between dead cell and phagocytes leading to efficient phagocytosis is divided in four steps: 1) attraction and accumulation of phagocytes to the site of apoptotic cells, 2) recognition and tethering, 3) internalization and 4) processing of dead cells within the phagocytes avoiding phlogosis. Apoptotic cells secrete chemotactic signals attracting phagocytes and expose on plasma membrane ligands mediating receptor-specific physical contact with phagocytes. Indeed, the subsequent internalization steps and outcomes, i.e. immunotolerance or immunomodulation, profoundly depend on the phagocytic receptors involved. PhotoDynamic Therapy (PDT), a promising new cancer treatment, is based on the synergic action of photosensitizing drugs (PS) and light irradiation that allow to kill the cells respectively via chemical and physical stress. Highly Reactive Oxygen Species (ROS), formed by the transfer of energy absorbed by PS upon irradiation to molecular oxygen, mediate the destruction of target cells. The best feature of PDT is the ROS damage directionality, depending on PS localization that in turn is mediated by its hydrophilicity/hydrophobicity, and the precise delivery of light to the treated sites. Multiple advantages characterize PDT as cancer treatment modality and make it potentially capable to meet many currently unmet medical needs. Particularly, PDT elicits a strong acute inflammation, orchestrated by both the innate and adaptive immune system, ensuring a protective effect by containing the disruption of tissue homeostasis and removal of damaged cells. The acute inflammatory response depends on photosensitized dead cells. Indeed, PDT not only induces apoptosis, autophagy and necrosis in the tumour cells, but it is also effective to rapidly generate an abundance of alarm/danger signals, called Damage-Associated Molecular Patterns (DAMPs), detected by the innate immunity alert elements. These, recruited to the sites of dead cells, eliminate injured and dead cells by phagocytosis and trigger the antitumour immunity by maturation and activation of dendritic cells (DCs). Here we will discuss whether the multiple PDT-induced cell death types can result in an immune response, linked to the exposure and/or release of signals by dying cells, ending in the phagocytosis by the immune cells. © 2013 by Nova Science Publishers, Inc. All rights reserved
In vitro and in vivo clearance of Rose Bengal Acetate-PhotoDynamic Therapy-induced autophagic and apoptotic cells
No full textIn vitro and in vivo clearance of Rose Bengal Acetate-PhotoDynamic Therapy-induced autophagic and apoptotic cells.
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Autophagy Contributes to the Death/Survival Balance in Cancer PhotoDynamic Therapy
No full textAutophagy is an important cellular program with a “double face” role, since it promotes either cell survival or cell death, also in cancer therapies. Its survival role occurs by recycling cell components during starvation or removing stressed organelles; when damage becomes extensive, autophagy provides another programmed cell death pathway, known as Autophagic Cell Death (ACD). The induction of autophagy is a common outcome in PhotoDynamic Therapy (PDT), a two-step process involving the irradiation of photosensitizer (PS)-loaded cancer cells. Upon tissue oxygen interaction, PS provokes immediate and direct Reactive Oxygen Species (ROS)-induced damage to Endoplasmic Reticulum (ER), mitochondria, plasma membrane, and/or lysosomes. The main biological effects carried out in cancer PDT are direct cytotoxicity to tumor cells, vasculature damage and induction of inflammatory reactions stimulating immunological responses. The question about the role of autophagy in PDT and its putative immunological impact is hotly controversial and largely studied in recent times. This review deals with the induction of autophagy in PDT protocols and its dual role, also considering its interrelationship with apoptosis, the preferential cell death program triggered in the photodynamic process
Timing the multiple cell death pathways initiated by Rose Bengal acetate photodynamic therapy
Full text linkRose Bengal Acetate PhotoDynamic Therapy (RBAc-PDT) induced multiple cell deaths pathways in HeLa cells through ROS generation. The onset of apoptosis, autophagy and of the different apoptotic pathways were timed by determining the levels of caspases, Bcl 2 family, Hsp 70, LC3, Grp78 and phospho-eIF2α proteins. Four different apoptotic pathways plus autophagy were sequentially initiated by RBAc-PDT: intrinsic, extrinsic, caspase 12- dependent and caspase independent as reflected by peaks of the relative caspases, 9, 8, 3 and 12. Autophagy, revealed by the formation of acidic autophagosomes and by increased Light Chain 3-II (LC3BII) expression was conspicuous at 8 h post-PDT. In our system, autophagy had a pro-death role, since its inhibitor, 3-MethylAdenine (3-MA), significantly augmented cell viability. The increase of cleaved caspase 12 was consequent to the increase of Grp78 and phospho-eIF2α proteins, suggesting Endoplasmic Reticulum. Regulation of the intrinsic pathway of apoptosis was under the control of Bcl-2 family (i.e. soon after irradiation Bcl2 decreased, Bax and tBid increased) and of Hsp70 proteins (peak at 12-18h post-PDT). Interestingly, inhibition of one pathway, i.e.caspase-9 (Z-LEHD-FMK), caspase-8 (Z-IETD-FMK), pan-caspases (Z-VAD-FMK), autophagy (3-MA) and necrosis (Nec-1), did not impair the activation of the others, suggesting the independent onset of the different apoptotic and autophagic pathways in a not subordinated fashion
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