Two combined photosensitizers: a goal for more effective photodynamic therapy of cancer (original) (raw)
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Differential cell photosensitivity following porphyrin photodynamic therapy
Cancer Research
Experiments were performed to determine if differences in porphyrin photosensitivity could be observed for cells with varying efficiency in DNA damage repair, as well as for cells which make up components of the vasculature. Photofrin II is undergoing current clinical evaluation for photodynamic therapy of solid tumors, and therefore the retention, dark toxicity, and photosensitizing effects of this drug on human DNA repairdeficient fibroblasts (ataxia telangiectasia and xeroderma pigmentosum) were compared to normal human fibroblasts. In addition, bovine cells of endothelial, smooth muscle, and fibroblast origin were compared for porphyrin retention, toxicity, and photosensitivity. All human fibroblasts exhibited porphyrin-induced dark toxicity, but there were no significant differences in photosensitization or porphyrin retention for any of these cell lines. However, bovine endothelial cells were considerably more photosensitive than smooth muscle or fibroblast cells treated under identical conditions. All bovine cells accumulated similar levels of por phyrin, and therefore the increased sensitivity of the endothelial cells was not due to differences in porphyrin retention. These results provide additional evidence that nuclear damage and/or repair is not a dominant factor in the cytotoxicity induced by porphyrin photosensitization. In addition, these results indicate that endothelial cell photosensitivity may play a role in the vascular damage observed following photodynamic therapy.
Molecular, cellular, and tissue responses following photodynamic therapy
Lasers in Surgery and Medicine, 1988
Photodynamic therapy (PDT) is being utilized in the treatment of a wide variety of malignant tumors. Results using PDT have been encouraging, and controlled clinical trials are currently being performed. The procedure exploits both the tumor-localizing and -photosensitizing properties of hematoporphyrin derivative or its purified component, Photofrin 11. When this porphyrin mixture is administered systemically, it is retained preferentially in tumor tissue as compared to surrounding normal tissue. Localized tumor destruction induced by PDT results from the photochemical generation of cytotoxic oxygen species within the tumor. This review will provide a summary of historical and current research pertaining to molecular, cellular, and tissue responses induced by PDT. Emphasis is placed on information related to the chemistry of current photosensitizers, subcellular targets, preclinical treatment parameters, and clinical responses following PDT.
Photodamaging Effects of Porphyrin in a Human Carcinoma Cell Line
The Chemical Educator, 2000
A convenient procedure to visualize the photodynamic effect of porphyrins on cell lines is shown. 5,10,15,20-Tetra(4-methoxyphenyl)porphyrin (TMP) was used as photosensitizer. The culture flasks bearing a Hep-2 cell line were incubated for 24 h with 1 µM of TMP. Under these conditions saturation of the TMP intracellular concentration is obtained. The irradiation of cell cultures for 30 min produces 90% cell mortality, while no toxicity was observed under dark conditions or under irradiation without TMP. This methodology can be used to demonstrate the photodynamic therapy (PDT) process in a laboratory experiment.
Investigational New Drugs, 2020
Photodynamic therapy (PDT) is gradually becoming an alternative method in the treatment of several diseases. Here, we investigated the role of oxygen in photodynamically treated cervical cancer cells (HeLa). The effect of PDT on HeLa cells was assessed by exposing cultured cells to disulphonated zinc phthalocyanine (ZnPcS 2) and tetrasulphonated zinc tetraphenylporphyrin (ZnTPPS 4). Fluorescence microscopy revealed their different localizations within the cells. ZnTPPS 4 seems to be mostly limited to the cytosol and lysosomes, whereas ZnPcS 2 is most likely predominantly attached to membrane structures, including plasmalemma and the mitochondrial membrane. Phototoxicity assays of PDT-treated cells carried out under different partial pressures of oxygen showed dose-dependent responses. Interestingly, ZnPcS 2 was also photodynamically effective at a minimal level of oxygen, under a nitrogen atmosphere. On the other hand, hyperbaric oxygenation did not lead to a higher PDT efficiency of either photosensitizer. Although both photosensitizers can induce a significant drop in mitochondrial membrane potential, ZnPcS 2 has a markedly higher effect on mitochondrial respiration that was completely blocked after two short light cycles. In conclusion, our observations suggest that PDT can be effective even in hypoxic conditions if a suitable sensitizer is chosen, such as ZnPcS 2 , which can inhibit mitochondrial respiration.
Efficient induction of apoptosis in HeLa cells by a novel cationic porphycene photosensitizer
European Journal of Medicinal Chemistry, 2013
In the present study we analyze the photobiological properties of 2,7,12-tris(a-pyridinio-p-tolyl)e17-(p-(methoxymethyl)phenyl) porphycene (Py 3 MeO-TBPo) in Hela cells, in order to assess its potential as a new photosensitizer for photodynamic therapy of cultured tumor cells. Using 0.5 mM Py 3 MeO-TBPo, flow cytometry studies demonstrated an increase of intracellular drug levels related to the incubation time, reaching a maximum at 18 h. LysoTracker Ò Green (LTG) and MitoTracker Ò Green (MTG) probes were used to identify the subcellular localization. Upon exposure to ultraviolet excitation, red porphycene fluorescence was detected as red granules in the cytoplasm that colocalized with LTG. No significant toxic effects were detected for Py 3 MeO-TBPo in the dark at concentrations below 1 mM. In contrast, Py 3 MeO-TBPo combined with red-light irradiation induced concentration-and fluence-dependent HeLa cells inactivation. Besides, all photodynamic protocols assayed induced a clear effect of cell detachment inhibition after trypsin treatment. Both apoptotic and necrotic cell death mechanisms can occur in HeLa cells depending on the experimental protocol. After 18 h incubation with 0.5 mM Py 3 MeO-TBPo and subsequent red light irradiation (3.6 J/cm 2 ), a high number of cells die by apoptosis, as evaluated by morphological alterations, immunofluorescent relocalization of Bax from cytosol to mitochondria, and TUNEL assay. Likewise, immunofluorescence techniques showed that cytochrome c is released from mitochondria into cytosol in cells undergoing apoptosis, which occurs immediately after relocation of Bax in mitochondria. The highest amount of apoptosis appeared 24 h after treatment (70%) and this cell death occurred without cell detachment to the substrate. In contrast, with 0.75 mM Py 3 MeO-TBPo and 3.6 J/cm 2 irradiation, morphological changes showed a preferential necrotic cell death.
Scientific reports, 2017
Cell death triggered by photodynamic therapy can occur through different mechanisms: apoptosis, necrosis or autophagy. However, recent studies have demonstrated the existence of other mechanisms with characteristics of both necrosis and apoptosis. These new cell death pathways, collectively termed regulated necrosis, include a variety of processes triggered by different stimuli. In this study, we evaluated the cell death mechanism induced by photodynamic treatments with two photosensitizers, meso-tetrakis (4-carboxyphenyl) porphyrin sodium salt (Na-H2TCPP) and its zinc derivative Na-ZnTCPP, in two human breast epithelial cell lines, a non-tumoral (MCF-10A) and a tumoral one (SKBR-3). Viability assays showed that photodynamic treatments with both photosensitizers induced a reduction in cell viability in a concentration-dependent manner and no dark toxicity was observed. The cell death mechanisms triggered were evaluated by several assays and cell line-dependent results were found. Mo...
Dyes and Pigments, 2001
The photodynamic behavior of 5,10,15,20-tetrakis(4-methoxyphenyl)porphyrin (TMP) has been investigated in solutions containing photo-oxidizable substrates and in the presence of Hep-2 human larynx-carcinoma cell line. It has been found that Hep-2 cells rapidly incorporate TMP until an intracellular concentration of $0.018 mmol of TMP/10 6 cells is reached. The survival of the irradiated cells treated with TMP was dependent upon both light exposure level and intracellular sensitizer concentration. In addition, a linear dependence of the photoinactivation rate (1/D 50 , where D 50 represents the light exposure level required to inactivate 50% of the cell population) and TMP intracellular concentration was found, indicating that TMP localizes at unsaturated sites within the cells. TMP photosensitized singlet molecular oxygen ( 1 Á 2 ) with a quantum yield of 0.65. When the amino acid l-tryptophan was used to assess 1 Á 2mediated photooxidation in a homogeneous medium, singlet molecular oxygen ( 1 Á g ) mediation appeared to be mainly responsible for the cell inactivation. These in vitro results enhance our understanding of the phototoxicity of porphyrins in cellular media and the sensitivity of Hep-2 cells to photodamage. #
Cancers, 2019
One of the most promising photosensitizers (PS) used in photodynamic therapy (PDT) is the porphyrin derivative 5,10,15,20-tetra(m-hydroxyphenyl)chlorin (mTHPC, temoporfin), marketed in Europe under the trade name Foscan®. A set of five human cancer cell lines from head and neck and other PDT-relevant tissues was used to investigate oxidative stress and underlying cell death mechanisms of mTHPC-mediated PDT in vitro. Cells were treated with mTHPC in equitoxic concentrations and illuminated with light doses of 1.8–7.0 J/cm2 and harvested immediately, 6, 24, or 48 h post illumination for analyses. Our results confirm the induction of oxidative stress after mTHPC-based PDT by detecting a total loss of mitochondrial membrane potential (Δψm) and increased formation of ROS. However, lipid peroxidation (LPO) and loss of cell membrane integrity play only a minor role in cell death in most cell lines. Based on our results, apoptosis is the predominant death mechanism following mTHPC-mediated ...