Phototoxic effectiveness of zinc phthalocyanine tetrasulfonic acid on MCF-7 cells with overexpressed P-glycoprotein (original) (raw)
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Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 2017
Doxorubicin is a broad-spectrum antibiotic and anticancer drug used to treat a variety of human malignancies like breast cancer and leukaemia. Unfortunately, a dose-dependent side effect of this drug is common, representing a major obstacle to its use despite its therapeutic efficacy. Photodynamic therapy is an emerging non-invasive potential adjuvant for conventional cancer treatment. In an attempt to circumvent the dose-limiting effect of doxorubicin, this study aimed to investigate cellular anticancer activity of doxorubicin and sulfonated zinc phthalocyanine-mediated photodynamic therapy on MCF-7 cells alone and in combination. Furthermore, we investigated the cell death pathway resulting from the combination treatment. MCF-7 cells were incubated with 0.5 µM concentration of doxorubicin for 20 h, afterwards, various concentrations of sulfonated zinc phthalocyanine were added and incubated for 4 h. Cells were irradiated using a 681.5 nm diode laser at 4.53 mW/cm2 for 18 min 24 s ...
International Journal of Cancer, 1997
The photodynamic properties and biodistribution pattern of zinc dodecafluoro-4-sulphophthalocyanine (ZnPcF 12 S 1 ), zinc hexadecafluorophthalocyanine (ZnPcF 16 ) and zinc phthalocyanine (ZnPc) were evaluated in the murine EMT-6 tumour model. All 3 dyes were formulated as a Cremophor oil-water emulsion after initial solubilization in methanol, acetone and pyridine, respectively. Comparison of their phototoxicity after in vitro incubation with EMT-6 cells and exposure to various fluences of red light showed that ZnPcF 12 S 1 is about 50 times more active than ZnPcF 16 , reflecting better cellpenetrating properties. Solubilisation of ZnPc in 1-methyl-2pyrrolidinone prior to formulation resulted in loss of photoactivity upon dilution in serum due to precipitation of the dye in the aqueous environment. In contrast, initial solubilisation in pyridine likely forms a ZnPc-pyridinium salt, and this preparation was 6 times more phototoxic than ZnPcF 12 S 1 . In vivo comparison of monosulphonated ZnPcF 12 S 1 with perfluorinated ZnPcF 16 showed improved pharmacokinetics in mice, including lower liver and spleen retentions and higher tumourto-non-target tissue ratios. However, photodynamic therapy (PDT) of the EMT-6 tumour in BALB/c mice with red light, 24 or 48 hr post-injection of 1 mmol · kg 21 of ZnPcF 12 S 1 induced mortality. Lowering the drug and/or light dose or extending the time interval between drug administration and irradiation to 72 hr avoided adverse effects but also resulted in poor tumour response. The best tumour control (25% of animals) was obtained at 0.1 µmol · kg 21 and a fluence of 400 J · cm 22 at 24 hr post-injection. In contrast, ZnPcF 16 required a 20-fold higher drug dose to induce a similar tumour response. The systemic shock following PDT with the amphiphilic ZnPcF 12 S 1 likely results from extensive cellular effects. Int.
Zinc phthalocyanines-mediated photodynamic therapy induces cell death in adenocarcinoma cells
Journal of Organometallic Chemistry, 2007
A panel of eight Zn-phthalocyanines (Zn-Pcs) (1)-(8), differently substituted on the benzo units, was synthesized either by direct cyclic-tetramerization of substituted phthalonitriles (compounds 1 and 2), or leading from the easily available tetrasulphonyl phthalocyanine to yield the sulfonamido derivatives 3 and 4, or else via the chloromethylation of precedent Zn-Pc followed by reaction with nucleophiles affording the dicationic Zn-Pcs and or the neutral Zn-Pcs and . The phototoxicity of these new compounds was evaluated in vitro on human colon adenocarcinoma cell line (HCT116), and their effect compared with those induced by porfimer sodium. The results are reported as IC 50 values, following exposure of the cells to different Zn-Pcs concentration and irradiation with a 500 W tungsten/halogen white lamp. The cationic Zn-Pc (5) and (6) together with the Zn-Pc (7), featuring 12 methoxy groups, were found good or fairly good photosensitizers while the more lipophilic Zn-Pcs (1)-(4) and (8) were found devoid of activity.
Photomedicine and Laser Surgery, 2008
Objective: The objective of this study was to investigate the cytotoxicity of octal-bromide zinc phthalocyanine (ZnPcBr 8) at different concentrations (0.25, 0.5, and 1 M) after irradiating HEp-2 cell cultures with two different light sources: a diode semiconductor laser (660 nm, 30 mW) or an LED (640 nm, 70 mW). In order to obtain comparative results, the irradiation parameters of both light sources were adjusted so that the amount of energy density delivered would be the same (4.5 J/cm 2). Background Data: Numerous photosensitizers and light sources used in the treatment of human disease have been studied. Based on these studies, a comparative evaluation of two light sources used in photodynamic therapy (PDT) with ZnPcBr 8 was proposed. Materials and Methods: HEp-2 cells were incubated with ZnPcBr 8 at different concentrations (0.25, 0.5, or 1 M) for 1 h, irradiated with the diode semiconductor laser (660 nm at 30 mW for 300 sec; 4.5 J/cm 2) or the LED laser (640 nm at 70 mW for 128 sec; 4.5 J/cm 2), and then incubated in MEM medium for 1 or 24 h. The cells were analyzed using the MTT and trypan blue dye exclusion tests. Results: The results demonstrated that the concentration of 1 M of ZnPcBr 8 was the most effective after PDT administered by both light sources. According to the MTT results, HEp-2-cell viability decreased by 97.96% 1 h after, and by 99.87% 24 h after irradiation with the diode semiconductor laser, and decreased by 94.03% 1 h after, and by 99.21% 24 h after irradiation with the LED. The results obtained using the trypan blue dye exclusion test confirmed the photodynamic efficacy of ZnPcBr 8 employed with both light sources. With regard to HEp-2-cell viability, the following results were observed: a decrease of 98.73% 1 h after, and of 99.49% 24 h after irradiation with the diode semiconductor laser; and a decrease of 98.76% 1 h after, and of 99.23% 24 h after irradiation with the LED. Conclusions: According to our results with the irradiation parameters studied here, both the LED and diode semiconductor laser can be used for PDT in vitro, since both light sources had excellent photodynamic efficacy.
Molecules
Multidrug resistance (MDR) has posed a significant threat to cancer treatment and has led to the emergence of a new therapeutic regime of photodynamic therapy (PDT) to curb the menace. The PDT modality employs a photosensitiser (PS), excited at a specific wavelength of light to kill cancer cells. In the present study, we used a zinc phthalocyanine tetrasulfonic acid PS to mediate the photodynamic killing of MCF-7 cells overexpressed with P-glycoprotein (P-gp) and investigate the response to cell death induction. After photodynamic treatment, MCF-7 cells undergo cell death, and indicators like Annexin V/PI staining, DNA fragmentation, and measurement of apoptotic protein expression were investigated. Results showed increased externalisation of phosphatidylserine protein, measured as a percentage in flow cytometry indicative of apoptotic induction. This expression was significant (p < 0.006) for the untreated control cells, and there was no detection of DNA fragments after a laser ...
Lysosomal and mitochondrial permeabilization mediates zinc(II) cationic phthalocyanine phototoxicity
The International Journal of Biochemistry & Cell Biology, 2013
In order to find a novel photosensitizer to be used in photodynamic therapy for cancer treatment, we have previously showed that the cationic zinc(II) phthalocyanine named Pc13, the sulfur-linked dye Q2 2,9(10),16(17),23(24)-tetrakis[(2-trimethylammonium) ethylsulfanyl]phthalocyaninatozinc(II) tetraioidide, exerts a selective phototoxic effect on human nasopharynx KB carcinoma cells and induces an apoptotic response characterized by an increase in the activity of caspase-3. Since the activation of an apoptotic pathway by chemotherapeutic agents contributes to the elimination of malignant cells, in this study we investigated the molecular mechanisms underlying the antitumor action of Pc13. We found that after light exposure, Pc13 induced the production of reactive oxygen species (ROS), which are mediating the resultant cytotoxic action on KB cells. ROS led to an early permeabilization of lysosomal membranes as demonstrated by the reduction of lysosome fluorescence with acridine orange and the release of lysosomal proteases to cytosol. Treatment with antioxidants inhibited ROS generation, preserved the integrity of lysosomal membrane and increased cell proliferation in a concentration-dependent manner. Lysosome disruption was followed by mitochondrial depolarization, cytosolic release of cytochrome C and caspases activation. Although no change in the total amount of Bax was observed, the translocation of Bax from cytosol to mitochondria, the cleavage of the pro-apoptotic protein Bid, together with the decrease of the anti-apoptotic proteins Bcl-X L and Bcl-2 indicated the involvement of Bcl-2 family proteins in the induction of the mitochondrial pathway. It was also demonstrated that cathepsin D, but not caspase-8, contributed to Bid cleavage. In conclusion, Pc13-induced cell photodamage is triggered by ROS generation and activation of the mitochondrial apoptotic pathway through the release of lysosomal proteases. In addition, our results also indicated that Pc13 induced a caspase-dependent apoptotic response, being activation of caspase-8,-9 and-3 the result of a post-mitochondrial event.
Liposome-bound Zn(II)-phthalocyanine. Mechanisms for cellular uptake and photosensitization
Journal of Photochemistry and Photobiology B: Biology, 1998
In the present study, cellular uptake of a liposomal formulation of ZnPc(CGP 55847) has been studied in human cervix carcinoma cells of the line NHIK 3025. The cellular uptake of ZnPc is found to be completed after 4-8 h of incubation. The maximum level of ZnPc in the cells after incubation with 1 p,g/ml ZnPc in E2a medium containing 3% serum is 60 ng/mg protein. The cellular uptake is attenuated by the presence of serum and at low temperature of the incubation medium, but the activation energy (30 kJ/mol) and fluorescence microscopic analysis of cells incubated with ZnPc at 0°C indicate that ZnPc is taken up into cells by a diffusion-mediated pathway. Measurements of subcellular marker enzymes have been performed immediately after light exposure of ZnPc-treated cells. The mitochondrial marker enzyme (cytochrome c oxidase) and the marker enzyme for the Golgi apparatus (UDP galactosyl transferase), but not those for lysosomes ([3-Nacetyl-D-glucosaminidase) and endoplasmic reticulum (NADPH cytochrome c reductase), are inactivated upon photodynamic treatment. These results indicate that ZnPc is mainly located in the Golgi apparatus and the mitochondria of NHIK 3025 cells. In contrast, photoactivated Photofrin is found to reduce the activity ofUDP galactosyl transferase, but not that ofNADPH cytochrome c reductase. The tetraphenylporphine TPPS/, and light reduce the activity of NADPH cytochrome c reductase, without influencing the activity of UDP galactosyl transferase. TPPS4 and light do not attenuate the activities of UDP galactosyl transferase and NADPH cytochrome c reductase.
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.
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...