Basic principles of photodynamic therapy

Photodynamic therapy (PDT), a treatment for cancer and for certain benign conditions, utilizes a photosensitizer and light to produce reactive oxygen in cells. PDT is primarily employed to kill tumor and other abnormal cells, so it is important to ask how this occurs. Many of the photosensitizers currently in clinical or pre-clinical studies of PDT localize in or have a major influence on mitochondria, and PDT is a strong inducer of apoptosis in many situations. The purpose of this review is to critically evaluate all of the recently published research on PDT-induced apoptosis, with a focus on studies providing mechanistic insights. Components of the mechanism whereby PDT causes cells to undergo apoptosis are becoming understood, as are the influences of several signal transduction pathways on the response. Future research should be directed to elucidating the role(s) of the multiple steps in apoptosis in directing damaged cells to an apoptotic vs. necrotic pathway
and for producing tumor ablation in conjunction with tissue-level mechanisms operating in vivo.

/pdf/the-role-of-apoptosis-in-response-to-photodynamic-therapy-2nu32e76t2.pdf

The role of apoptosis in response to photodynamic therapy: what, where, why, and how

Reactive oxygen or nitrogen species (ROS/RNS) generated endogenously or in response to environmental stress have long been implicated in tissue injury in the context of a variety of disease states. ROS/RNS can cause cell death by nonphysiological (necrotic) or regulated pathways (apoptotic). The mechanisms by which ROS/RNS cause or regulate apoptosis typically include receptor activation, caspase activation, Bcl-2 family proteins, and mitochondrial dysfunction. Various protein kinase activities, including mitogen-activated protein kinases, protein kinases-B/C, inhibitor-of-I-κB kinases, and their corresponding phosphatases modulate the apoptotic program depending on cellular context. Recently, lipid-derived mediators have emerged as potential intermediates in the apoptosis pathway triggered by oxidants. Cell death mechanisms have been studied across a broad spectrum of models of oxidative stress, including H2O2, nitric oxide and derivatives, endotoxin-induced inflammation, photodynamic therapy, ultraviole...

Mechanisms of cell death in oxidative stress.

Singlet molecular oxygen, 02(’Ag) , has been intensively investigated over the last few decades, primarily in relation to photosensitization reactions. In combination with the increasing awareness and interest in singlet oxygen has been the development of various methodologies for the detection and quantification of singlet oxygen production. A large body of literature now exists concerning the singlet oxygengenerating abilities of a large variety of endogenous and exogenous compounds that can be photoactivated in the UV and visible regions of the electromagnetic spectrum. The purpose of this review was to compile data from many different sources to provide a convenient resource for biological scientists with interest in this area. This compilation is essentially an updated subset of the excellent comprehensive review on singlet oxygen yields by Wilkinson et af. (l), which, unlike this compilation, was not limited to biological molecules. The data are current up to the early months of 1999. The following tables include various related parameters in addition to the central parameter of the quantum yield of singlet oxygen generation (QA) for a given photosensitizer. The methodology or technique used to measure the QA value for each entry is given and ranges from direct detection of the luminescence produced on relaxation of singlet oxygen (time-resolved [TRILIT or steady-state [SSIL]), calorimetric

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1751-1097.1999.tb08240.x

A Compilation of Singlet Oxygen Yields from Biologically Relevant Molecules

Metal Complexes as Photo- and Radiosensitizers

Four silicon phthalocyanine photosensitizers have been prepared and studied in an effort to learn more about the structural features that a silicon phthalocyanine must have in order to be a good photodynamic therapy (PDT) photosensitizer. The compounds that have been studied are the known phthalocyanines HOSiPcOSi(CH3)2-(CH2)3N(CH3)2, Pc 4; and SiPc[OSi(CH3)2(CH2)3N(CH3)2]2, Pc 12; and the new photosensitizers HOSiPcOSi(CH3)2- (CH2)3N(CH2CH3)(CH2)2N(CH3)2, Pc 10; and SiPc[OSi (CH3)2(CH2)3N(CH2CH3)(CH2)2N(CH3)2]2, Pc 18. The triplet lifetimes of the four photosensitizers, their singlet oxygen quantum yields, their ability to photoenhance the generation of lipid peroxidation products in human erythrocyte ghosts, their ability to partition into V79 cells and their ability to photokill V79 and L5178Y-R cells have been determined. It is concluded that the presence of a small axial ligand (e.g. an OH ligand) is not necessary for efficient photosensitization, the presence of two aminosiloxy ligands generally provides at least as good photosensitization as one such ligand, and the presence of an elongated diaminosiloxy axial ligand rather than a short aminosiloxy ligand is less desirable. Further, it is concluded that the presence of structural features leading to improvement in the association between the photosensitizers and important cellular targets are more useful than those leading to improvements in their already acceptable photophysical and photochemical properties.

The Synthesis, Photophysical and Photobiological Properties and in vitro Structure-Activity Relationships of a Set of Silicon Phthalocyanine PDT Photosensitizers

Apoptosis induced by numerous cancer chemotherapeutic and other toxic agents has been shown to proceed through a cascade of proteases, now termed caspases, culminating in cleavage of a set of proteins. The ability of photodynamic treatment (PDT) with the phthalocyanine Pc 4 to activate cellular caspases has been assessed during the rapid apoptosis in murine lymphoma L5178Y-R cells. Cells were exposed to combinations of Pc 4 and activating red light that result in ≥90% cell death, as judged by a clonogenic assay. The rate of entry of cells into apoptosis was dose dependent. For 0.5 µm Pc 4 and either 2.1 or 3 kJ/m2, which kill 90 or 99.9% of the cells, oligonucleosomal fragmentation was visible on agarose gels as early as 60 or 30 min after PDT, respectively. To assess caspase activation, cells were harvested at various times after PDT, and cell proteins were subjected to electrophoresis and Western blot analysis, using an antibody to poly(ADP-ribose) polymerase (PARP). The cleavage of the normally Mr 116,000 PARP into fragments of Mr ∼90,000 was observed at approximately the same time as the earliest DNA fragmentation. An antibody to the polymer, poly(ADP-ribose), did not recognize the Mr ∼90,000 PARP cleavage products, in contrast to the parent enzyme. This analysis also revealed that levels of a poly(ADP-ribosylated) Mr 100,000 protein, tentatively identified as topoisomerase I, were maintained in cells after PARP was fully cleaved. Caspase-3 (and/or caspase-7) activity, as measured in cell lysates with the fluorogenic substrate DEVD-AMC, was elevated almost immediately after PDT. The cell-permeable, irreversible caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp(O-methyl)-fluoro-methylketone, inhibited PDT-induced apoptosis and PARP cleavage, whereas the inactive peptide analogue, benzyloxycarbonyl-Phe-Ala-fluoromethyl ketone, was without effect. The results indicate that PDT-induced apoptosis is mediated by activation of caspase-3 and/or other similar caspases.

https://cancerres.aacrjournals.org/content/canres/58/5/940.full.pdf

Protease activation and cleavage of poly(ADP-ribose) polymerase: an integral part of apoptosis in response to photodynamic treatment.

Prostate carcinoma (PCA) is the most frequently diagnosed malignancy in American men. PCA at advanced stages can both proliferate abnormally and resist apoptosis. Among the many known signal transduction pathways, phosphatidylinositide-3'OH kinase (PI3-kinase) has been shown to play an important role in cell survival and resistance to apoptosis. In this study, we investigate the involvement of Etk/Bmx, a newly discovered tyrosine kinase that is a substrate of PI3-kinase, in protection of prostate cancer cells from apoptosis. Parental LNCaP cells and two derivative cell lines, one overexpressing wild type Etk (Etkwt) and the other expressing a dominant negative Etk (EtkDN), were used to study the function of Etk. The cells were treated with photodynamic therapy (PDT), a newly approved cancer treatment which employs a photosensitizer and visible light to produce an oxidative stress in cells, often leading to apoptosis. Our results indicate that PDT induces apoptosis in LNCaP cells, as measured by DNA fragmentation and by cleavage of poly(ADP-ribose) polymerase (PARP), and moreover, the extent of apoptosis was much reduced in Etkwt cells as compared to LNCaP or EtkDN cells. Assay of overall cell viability confirmed that Etkwt cells were considerably less sensitive to PDT than were the parental LNCaP or EtkDN cells. Similar results were found in response to thapsigargin (TG). A specific inhibitor of PI3-kinase, LY294002, abolished Etk activity and markedly increased TG-induced PARP cleavage. The results suggest that Etk/Bmx is an efficient effector of PI3-kinase and that the newly described PI3-kinase/Etk pathway is involved in the protection of prostate carcinoma cells from apoptosis in response to PDT or TG.

Etk/Bmx, a PH-domain containing tyrosine kinase, protects prostate cancer cells from apoptosis induced by photodynamic therapy or thapsigargin

Photodynamic therapy (PDT), a cancer treatment that employs a photosensitizer and visible light, induces apoptosis in murine LY-R leukemic lymphoblasts and in CHO cells, but the rate and extent of apoptosis are much greater in LY-R cells. Three MAPK family members, ERK1/ERK2, SAPK/JNK, and p38/HOG, are important intermediates in signal transduction pathways. To ascertain whether activation of one or more MAPKs could mediate PDT-induced apoptosis, Western blot analysis has been performed on the proteins of LY-R and CHO cells at various times following lethal (90 - 99% cell kill) doses of PDT photosensitized by the phthalocyanine Pc 4. The blots were probed with antibodies to each of the proteins as well as antibodies specific for the activated (phosphorylated) forms of each kinase. Of the three MAPK types, only the p46 and p54 SAPK/JNKs were found to be activated by PDT in LY-R cells, with a maximum approximately threefold increase in the content of the phosphorylated forms reached in 30 - 60 min. An even larger relative activation was observed in CHO cells. PDT did not affect ERK and p38/HOG activation in LY-R cells. In the case of CHO cells, however, ERK2 was slightly activated at 5 min post-PDT, then declined, and p38/HOG was strongly activated from 5 to 60 min post-PDT. A specific inhibitor (PD98059) of MEK1, the kinase that activates ERK, had little or no effect on PDT-induced apoptosis in either LY-R or CHO cells. In contrast, a specific inhibitor of p38/HOG (SB202190) blocked PDT-induced apoptosis in LY-R cells with a lesser effect in CHO cells. The results suggest that both the SAPK and p38/HOG cascades can be stimulated by PDT and that the latter participates in both rapid and slow PDT-induced apoptosis. Furthermore, the high level of constitutively active p38/HOG in LY-R cells may poise those cells for rapid activation of apoptosis following PDT.

/pdf/promotion-of-photodynamic-therapy-induced-apoptosis-by-utw04jnbxn.pdf

Promotion of photodynamic therapy-induced apoptosis by stress kinases.

Photodynamic therapy, a novel cancer treatment using a photosensitive dye and visible light, produces an oxidative stress in cells, often leading to apoptotic cell death. Because ceramide is a second messenger that has been associated with stress-induced apoptosis, we investigated a possible link between photodynamic treatment (PDT), ceramide, and apoptosis in L5178Y-R (LY-R) cells. The cells undergo rapid apoptosis, initiating within 30 min of PDT. After a dose of PDT producing a 99.9% loss of clonogenicity, LY-R cells responded by an increased production of ceramide, which reached a maximum level in 60 min. For a constant light fluence and varying concentrations of the phthalocyanine photosensitizer Pc 4 [HOSiPcOSi(CH3)2(CH2)3N(CH3)2], the ED50 for ceramide generation (46 nm) was similar to the LD50 for clonogenic cell death (40 nm). We suggest that the PDT-stimulated increase in synthesis of ceramide in LY-R cells may be coupled to PDT-induced apoptosis. When the cells were exposed to exogenous N-acetyl-sphingosine (10 µm), apoptotic changes were observed only after 12–24 h. The delayed apoptotic response to the synthetic ceramide may be due to an induction of apoptosis by a different route than the one used by PDT.

/pdf/ceramide-generation-in-response-to-photodynamic-treatment-of-1i8fp0ayhn.pdf

Ceramide generation in response to photodynamic treatment of L5178Y mouse lymphoma cells.

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