Photoactivated hypericin is not genotoxic

Feruszova, Jana; Imreova, Petronela; Bodnarova, Kristina; Ševčovičová, Andrea; Kyzek, Stanislav; Chalupa, Ivan; Gálová, Eliška; Miadoková, Eva

doi:10.4149/gpb_2015045

Cited by 11 publications

(9 citation statements)

References 28 publications

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“…HY was applied in the concentration range of 0–150 nM and HP in the range of 0.5–50 µM. It is known that HY in the dark possesses zero or minimal toxicity [27,28,29,30,31]. Some biological effects on more sensitive cancer cell lines were described after the application of approximately eight times higher concentrations of non-photoactivated HY than our highest concentration was (150 nM).…”

Section: Resultsmentioning

confidence: 83%

Novel Insights into the Effect of Hyperforin and Photodynamic Therapy with Hypericin on Chosen Angiogenic Factors in Colorectal Micro-Tumors Created on Chorioallantoic Membrane

Majerník

Jendželovský

Babinčák

et al. 2019

IJMS

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Photodynamic therapy with hypericin (HY-PDT) and hyperforin (HP) could be treatment modalities for colorectal cancer (CRC), but evidence of their effect on angiogenic factors in CRC is missing. Convenient experimental model utilization is essential for angiogenesis research. Therefore, not only 2D cell models, but also 3D cell models and micro-tumors were used and compared. The micro-tumor extent and interconnection with the chorioallantoic membrane (CAM) was determined by histological analyses. The presence of proliferating cells and HY penetration into the tumor mass were detected by fluorescence microscopy. The metabolic activity status was assessed by an colorimetric assay for assessing cell metabolic activity (MTT assay) and HY accumulation was determined by flow cytometry. Pro-angiogenic factor expression was determined by Western blot and quantitative real-time polymerase chain reaction (RT-qPCR). We confirmed the cytotoxic effect of HY-PDT and HP and showed that their effect is influenced by structural characteristics of the experimental model. We have pioneered a method for analyzing the effect of HP and cellular targeted HY-PDT on pro-angiogenic factor expression in CRC micro-tumors. Despite the inhibitory effect of HY-PDT and HP on CRC, the increased expression of some pro-angiogenic factors was observed. We also showed that CRC experimental micro-tumors created on quail CAM could be utilized for analyses of gene and protein expression.

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Section: Resultsmentioning

confidence: 83%

Novel Insights into the Effect of Hyperforin and Photodynamic Therapy with Hypericin on Chosen Angiogenic Factors in Colorectal Micro-Tumors Created on Chorioallantoic Membrane

Majerník

Jendželovský

Babinčák

et al. 2019

IJMS

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“…In our study, e.g., few micromolar H 2 O 2 on 250,000 cells were sufficient to induce cell death. The concentrations of, e.g., H 2 O 2 used in many genotoxicity studies are 10-50-fold higher at lower absolute cell numbers [66–68]. So far, only few studies in plasma medicine investigated genotoxicity in cells and tissues using non- γ H2AX assays, and the once that have did not report mutagenic effects of plasma treatment.…”

Section: Discussionmentioning

confidence: 99%

Elevated H2AX Phosphorylation Observed with kINPen Plasma Treatment Is Not Caused by ROS-Mediated DNA Damage but Is the Consequence of Apoptosis

Bekeschus

Schütz

Nießner

et al. 2019

Oxidative Medicine and Cellular Longevity

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Phosphorylated histone 2AX (γH2AX) is a long-standing marker for DNA double-strand breaks (DSBs) from ionizing radiation in the field of radiobiology. This led to the perception of γH2AX being a general marker of direct DNA damage with the treatment of other agents such as low-dose exogenous ROS that unlikely act on cellular DNA directly. Cold physical plasma confers biomedical effects majorly via release of reactive oxygen and nitrogen species (ROS). In vitro, increase of γH2AX has often been observed with plasma treatment, leading to the conclusion that DNA damage is a direct consequence of plasma exposure. However, increase in γH2AX also occurs during apoptosis, which is often observed with plasma treatment as well. Moreover, it must be questioned if plasma-derived ROS can reach into the nucleus and still be reactive enough to damage DNA directly. We investigated γH2AX induction in a lymphocyte cell line upon ROS exposure (plasma, hydrogen peroxide, or hypochlorous acid) or UV-B light. Cytotoxicity and γH2AX induction was abrogated by the use of antioxidants with all types of ROS treatment but not UV radiation. H2AX phosphorylation levels were overall independent of analyzing either all nucleated cells or segmenting γH2AX phosphorylation for each cell cycle phase. SB202190 (p38-MAPK inhibitor) and Z-VAD-FMK (pan-caspase inhibitor) significantly inhibited γH2AX induction upon ROS but not UV treatment. Finally, and despite γH2AX induction, UV but not plasma treatment led to significantly increased micronucleus formation, which is a functional read-out of genotoxic DNA DSBs. We conclude that plasma-mediated and low-ROS γH2AX induction depends on caspase activation and hence is not the cause but consequence of apoptosis induction. Moreover, we could not identify lasting mutagenic effects with plasma treatment despite phosphorylation of H2AX.

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“…Hypericin possesses several properties that make it a powerful fluorescent photosensitizer that is suitable for PDT and PDD—attractive applications for the treatment and detection of tumors. It possesses minimal or no toxicity in the dark (Thomas and Pardini, 1992 ; Vandenbogaerde et al, 1997 ; Miadokova et al, 2010 ; Jendželovská et al, 2014 ; Feruszová et al, 2016 ), accumulates preferentially in neoplastic tissues (Kamuhabwa et al, 2002 ; Noell et al, 2011 ) and generates reactive oxygen species (ROS) in the presence of light (at wavelengths around 600 nm) and oxygen (Diwu and Lown, 1993 ). Thus, hypericin represents a potent natural alternative to chemically synthesized photosensitizers.…”

Section: Light-activated Hypericinmentioning

confidence: 99%

Hypericin in the Light and in the Dark: Two Sides of the Same Coin

et al. 2016

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Hypericin (4,5,7,4′,5′,7′-hexahydroxy-2,2′-dimethylnaphtodianthrone) is a naturally occurring chromophore found in some species of the genus Hypericum, especially Hypericum perforatum L. (St. John's wort), and in some basidiomycetes (Dermocybe spp.) or endophytic fungi (Thielavia subthermophila). In recent decades, hypericin has been intensively studied for its broad pharmacological spectrum. Among its antidepressant and light-dependent antiviral actions, hypericin is a powerful natural photosensitizer that is applicable in the photodynamic therapy (PDT) of various oncological diseases. As the accumulation of hypericin is significantly higher in neoplastic tissue than in normal tissue, it can be used in photodynamic diagnosis (PDD) as an effective fluorescence marker for tumor detection and visualization. In addition, light-activated hypericin acts as a strong pro-oxidant agent with antineoplastic and antiangiogenic properties, since it effectively induces the apoptosis, necrosis or autophagy of cancer cells. Moreover, a strong affinity of hypericin for necrotic tissue was discovered. Thus, hypericin and its radiolabeled derivatives have been recently investigated as potential biomarkers for the non-invasive targeting of tissue necrosis in numerous disorders, including solid tumors. On the other hand, several light-independent actions of hypericin have also been described, even though its effects in the dark have not been studied as intensively as those of photoactivated hypericin. Various experimental studies have revealed no cytotoxicity of hypericin in the dark; however, it can serve as a potential antimetastatic and antiangiogenic agent. On the contrary, hypericin can induce the expression of some ABC transporters, which are often associated with the multidrug resistance (MDR) of cancer cells. Moreover, the hypericin-mediated attenuation of the cytotoxicity of some chemotherapeutics was revealed. Therefore, hypericin might represent another St. John's wort metabolite that is potentially responsible for negative herb–drug interactions. The main aim of this review is to summarize the benefits of photoactivated and non-activated hypericin, mainly in preclinical and clinical applications, and to uncover the “dark side” of this secondary metabolite, focusing on MDR mechanisms.

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Photoactivated hypericin is not genotoxic

Cited by 11 publications

References 28 publications

Novel Insights into the Effect of Hyperforin and Photodynamic Therapy with Hypericin on Chosen Angiogenic Factors in Colorectal Micro-Tumors Created on Chorioallantoic Membrane

Novel Insights into the Effect of Hyperforin and Photodynamic Therapy with Hypericin on Chosen Angiogenic Factors in Colorectal Micro-Tumors Created on Chorioallantoic Membrane

Elevated H2AX Phosphorylation Observed with kINPen Plasma Treatment Is Not Caused by ROS-Mediated DNA Damage but Is the Consequence of Apoptosis

Hypericin in the Light and in the Dark: Two Sides of the Same Coin

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