Effects of zinc porphyrin and zinc phthalocyanine derivatives in photodynamic anticancer therapy under different partial pressures of oxygen in vitro (original) (raw)
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Journal of photochemistry and photobiology. B, Biology, 2017
Cervical cancer is the most common gynecological malignancy worldwide, and the leading cause of cancer related deaths among females. Conventional treatment for early cervical cancer is radical hysterectomy. In locally advanced cancer the treatment of choice is concurrent chemo radiation. Although such treatment methods show promise, they do have adverse side effects. To minimize these effects, as well as prevent cancer re-occurrence, new treatment methods are being investigated. Photodynamic therapy (PDT) involves the selective uptake of a photosensitizer (PS) by cancer cells, illumination with light of an appropriate wavelength that triggers a photochemical reaction leading to the generation of reactive oxygen and subsequent tumor regression. The effect of PDT on a cervical cancer cell line (HeLa) was assessed by exposing cultured cells to a sulphonated zinc phthalocyanine PS (ZnPcS) and irradiating the cells using a 673nm diode laser. The effects were measured using the Trypan blu...
Two combined photosensitizers: a goal for more effective photodynamic therapy of cancer
Cell death & disease, 2014
Photodynamic therapy (PDT) is a clinically approved therapeutic modality for the treatment of diseases characterized by uncontrolled cell proliferation, mainly cancer. It involves the selective uptake of a photosensitizer (PS) by neoplastic tissue, which is able to produce reactive oxygen species upon irradiation with light, leading to tumor regression. Here a synergistic cell photoinactivation is reported based on the simultaneous administration of two PSs, zinc(II)-phthalocyanine (ZnPc) and the cationic porphyrin meso-tetrakis(4-N-methylpyridyl)porphine (TMPyP) in three cell lines (HeLa, HaCaT and MCF-7), using very low doses of PDT. We detected changes from predominant apoptosis (without cell detachment) to predominant necrosis, depending on the light dose used (2.4 and 3.6 J/cm(2), respectively). Analysis of changes in cytoskeleton components (microtubules and F-actin), FAK protein, as well as time-lapse video microscopy evidenced that HeLa cells were induced to undergo apoptosi...
Chemico-Biological Interactions, 2009
PDT has been used in the treatment of malignant brain tumors for the last 2 decades. It is based on the interaction of a photosensitizer (PS) and light of an appropriate wavelength, with generation of oxygen species, mainly singlet oxygen. Brain is particularly susceptible to oxidative stress; therefore the study of PDT effects on cerebral mitochondria might provide mechanistic insights into the action of the therapy, contributing to its optimization. In the present study, we addressed the mitochondrial toxicity of the second generation PS, zinc phthalocyanine tetrasulfonate (ZnPcS 4 ), on rat brain isolated mitochondria, by investigating both intrinsic toxicity and photodynamic action. At higher concentrations (15 and 25 M/mg protein) ZnPcS 4 caused (a) inhibition of state-3 respiration and (b) decrease of RCR and ADP/O. Electrochemical potential, state-4 respiration and Ca 2+ retention capacity were not affected. Cytochrome c release was not observed. Coupled with 600 or 1800 mJ/cm 2 laser irradiation, ZnPcS 4 (5 M/mg protein) caused more intense effects on state 3, RCR and ADP/O; moreover state-4 respiration and membrane potential were affected. Besides that, Ca 2+ and cytochrome c release were induced. Cyclosporine A (CsA) decreased Ca 2+ release and ameliorated the electrochemical potential, suggesting that membrane permeability transition (MPT) might be involved in the photodynamic effect. The low intrinsic toxicity and the high photodynamic effect on rat brain mitochondria induced by ZnPcS 4 , allied to its improved photophysical properties, might indicate its potential for the treatment of malignant brain tumors.
International Journal of Oncology, 2017
Photodynamic therapy (PDT) has gathered much attention in the field of cancer treatment and is increasingly used as an alternative solution for esophageal cancer therapy. However, there is a constant need for improving the effectiveness and tolerability of the applied photosensitizers (PS). Here, we propose tetra-triethyleneoxysulfonyl substituted zinc phthalocyanine (ZnPc) as a promising PS for photodynamic treatment of esophageal cancer. ZnPc-induced phototoxicity was studied in two human esophageal cancer cell lines: OE-33 (adenocarcinoma) and Kyse-140 (squamous cell carcinoma). In vitro studies focused on the uptake and intracellular distribution of the novel ZnPc as well as on its growth inhibitory potential, reactive oxygen species (ROS) formation and the induction of apoptosis. The chicken chorioallantoic membrane assay (CAM assay) and studies on native Wistar rats were employed to determine the antineoplastic and antiangiogenic activity of ZnPc-PDT as well as the tolerability and safety of non-photoactivated ZnPc in vivo. ZnPc was taken up by cancer cells in a dose-and time-dependent manner and showed a homogeneous cytoplasmic distribution. Photoactivation of ZnPc-loaded (1-10 µM) cells led to a dose-dependent growth inhibition of esophageal adenocarcinoma and squamous cell carcinoma cells of >90%. The antiproliferative effect was based on ROS-induced cytotoxicity and the induction of mitochondria-driven apoptosis. In vivo studies on esophageal tumor plaques grown on the CAM revealed pronounced antiangiogenic and antineoplastic effects. ZnPc-PDT caused long-lasting changes in the vascular architecture and a marked reduction of tumor feeding blood vessels. Animal studies confirmed the good tolerability and systemic safety of ZnPc, as no changes in immunological, behavioral and organic parameters could be detected upon treatment with the nonphotoactivated ZnPc. Our findings show the extraordinary photoactive potential of the novel ZnPc as a photosensitizer for PDT of esophageal cancer.
Mechanism and Efficiency of Cell Death of Type II Photosensitizers: Effect of Zinc Chelation†
Photochemistry and Photobiology, 2012
A series of meso-substituted tetra-cationic porphyrins, which have methyl and octyl substituents, was studied in order to understand the effect of zinc chelation and photosensitizer subcellular localization in the mechanism of cell death. Zinc chelation does not change the photophysical properties of the photosensitizers (all molecules studied are type II photosensitizers) but affects considerably the interaction of the porphyrins with membranes, reducing mitochondrial accumulation. The total amount of intracellular reactive species induced by treating cells with photosensitizer and light is similar for zinc-chelated and free-base porphyrins that have the same alkyl substituent. Zinc-chelated porphyrins, which are poorly accumulated in mitochondria, show higher efficiency of cell death with features of apoptosis (higher MTT response compared with trypan blue staining, specific acridine orange ⁄ ethidium bromide staining, loss of mitochondrial transmembrane potential, stronger cytochrome c release and larger sub-G1 cell population), whereas nonchelated porphyrins, which are considerably more concentrated in mitochondria, triggered mainly necrotic cell death. We hypothesized that zinc-chelation protects the photoinduced properties of the porphyrins in the mitochondrial environment.
Lékař a technika - Clinician and Technology, 2019
This study deals with the utilization of photosensitizer (λmax ~ 660 nm) from the group of the phthalocyanines, in photodynamic therapy. Effect of the zinc phthalocyanine photosensitizer mediated photodynamic therapy was evaluated in vitro on the tumor cell line – HeLa (cervical cancer cells) using mass spectrometry and atomic force and fluorescent microscopy techniques.
PloS one, 2014
Mitochondria play a key role in aerobic ATP production and redox control. They harness crucial metabolic pathways and control cell death mechanisms, properties that make these organelles essential for survival of most eukaryotic cells. Cancer cells have altered cell death pathways and typically show a shift towards anaerobic glycolysis for energy production, factors which point to mitochondria as potential culprits in cancer development. Targeting mitochondria is an attractive approach to tumor control, but design of pharmaceutical agents based on rational approaches is still not well established. The aim of this study was to investigate which structural features of specially designed Zn(II)N-alkylpyridylporphyrins would direct them to mitochondria and to particular mitochondrial targets. Since Zn(II)N-alkylpyridylporphyrins can act as highly efficient photosensitizers, their localization can be confirmed by photodamage to particular mitochondrial components. Using cultured LS174T a...
2005
We have developed a totally new class of nonporphyrin photodynamic therapeutic agents with a specific focus on two lead candidates azadipyrromethene (ADPM)01 and ADPM06. Confocal laser scanning microscopy imaging showed that these compounds are exclusively localised to the cytosolic compartment, with specific accumulation in the endoplasmic reticulum and to a lesser extent in the mitochondria. Light-induced toxicity assays, carried out over a broad range of human tumour cell lines, displayed EC 50 values in the micro-molar range for ADPM01 and nano-molar range for ADPM06, with no discernable activity bias for a specific cell type. Strikingly, the more active agent, ADPM06, even retained significant activity under hypoxic conditions. Both photosensitisers showed low to nondeterminable dark toxicity. Flow cytometric analysis revealed that ADPM01 and ADPM06 were highly effective at inducing apoptosis as a mode of cell death. The photophysical and biological characteristics of these PDT agents suggest that they have potential for the development of new anticancer therapeutics.
Zinc Trisulphonated Phthalocyanine Used in Photodynamic Therapy of Dysplastic Oral Keratinocytes
Revista de Chimie -Bucharest- Original Edition-
Photodynamic therapy is an alternative antitumoral procedure that requires the use of a photosensitiser and a light source emitting radiation with an adequate wavelength, suitable for activating the photosensitiser; the most common photosensitisers are porphyrins and porphyrin-related substances. Phthalocyanines are macrocyclic chemical compounds structurally related to the porphyrins, as they both feature four linked pyrrole-like subunits, therefore possessing the potential of acting as good photosensitisers; metallo- substituted sulphonated phthalocyanines are novel chemical compounds that revealed promising results when used in PDT. Activated photosensitisers can lead to the destruction of the tumoral cells through production of reactive oxygen species and the induction of apoptosis. The present study aims to assess, via protein microarray analysis, the main molecular pathways involved in the apoptosis of dysplastic oral keratinocytes following photodynamic therapy using zinc tri...
Cancer research, 2001
Photodynamic therapy (PDT) of tumors and other diseases is based on the uptake of a photosensitizing dye in target cells, which are damaged by reactive oxygen intermediates generated on irradiation with light in which the wavelengths match the dye absorption spectrum. PDT can induce cell death by necrosis and apoptosis both in vivo and in vitro, but the factors determining the contribution of either mechanism to the overall process are not completely defined. Our studies on the photosensitization of 4R transformed fibroblasts with the second-generation photosensitizer zinc (II) phthalocyanine (ZnPc) aim at determining the effect of important experimental parameters such as time of cell incubation (2 or 24 h) with ZnPc before irradiation and ZnPc concentration in the incubation medium on cell death. Furthermore, we propose possible correlations between the cell death mechanism and primary photo-damage sites; these are mainly determined by the intracellular localization of the photose...