Importance of Hypericin-Bcl2 interactions for biological effects at subcellular levels

Štroffeková, Katarína; Tomkova, Silvia; Huntošová, Veronika; Kožár, Tibor

doi:10.1016/j.pdpdt.2019.08.016

Cited by 8 publications

(14 citation statements)

References 112 publications

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“…In this work, we have investigated further the interaction of Hyp, a naturally occurring compound, with anti-apoptotic Bcl-2 family members Bcl-2 and Mcl-1. As shown earlier, Hyp interacted with BH1 and BH3 peptides of Bcl-2 protein similar to known Bcl-2 inhibitor ABT263, and our QPLD docking data indicated that Hyp could interact with Bcl-2 and Mcl-1 similar to pan-Bcl-2 BH3 mimetic, Goss (Stroffekova et al, 2019).…”

Section: Discussionsupporting

confidence: 78%

“…It has been claimed that Hyp and its derivates are compounds with a minimal cytotoxicity prior to illumination (Miskovsky, 2002;Theodossiou et al, 2009). However, there is growing evidence to contrary, including our recent work (Martinez-Poveda et al, 2005;Gyenge et al, 2013;Larisch et al, 2013;Larisch et al, 2014;Huntosova et al, 2017;Stroffekova et al, 2019). It has been shown that Hyp can accumulate in normal and tumor mammalian cells at a similar level and can display light-independent cytotoxicity in a wide range of concentrations (Blank et al, 2004;Mandel et al, 2007).…”

Section: Introductionmentioning

confidence: 94%

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Hypericin, a potential new BH3 mimetic

et al. 2022

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Many types of cancer such as prostate cancer, myeloid leukemia, breast cancer, glioblastoma display strong chemo resistance, which is supported by enhanced expression of multiple anti-apoptotic Bcl-2, Bcl-XL and Mcl-1 proteins. The viable anti-cancer strategies are based on developing anti-apoptotic Bcl-2 proteins inhibitors, BH3 mimetics. Our focus in past years has been on the investigating a new potential BH3 mimetic, Hypericin (Hyp). Hyp is a naturally occurring photosensitive compound used in photodynamic therapy and diagnosis. We have demonstrated that Hyp can cause substantial effects in cellular ultrastructure, mitochondria function and metabolism, and distribution of Bcl2 proteins in malignant and non-malignant cells. One of the possible mechanisms of Hyp action could be the direct interactions between Bcl-2 proteins and Hyp. We investigated this assumption by in silico computer modelling and in vitro fluorescent spectroscopy experiments with the small Bcl2 peptide segments designed to correspond to Bcl2 BH3 and BH1 domains. We show here that Hyp interacts with BH3 and BH1 peptides in concentration dependent manner, and shows the stronger interactions than known BH3 mimetics, Gossypol (Goss) and ABT-263. In addition, interactions of Hyp, Goss and ABT263, with whole purified proteins Bcl-2 and Mcl-1 by fluorescence spectroscopy show that Hyp interacts stronger with the Bcl-2 and less with Mcl-1 protein than Goss or ABT-263. This suggest that Hyp is comparable to other BH3 mimetics and could be explore as such. Hyp cytotoxicity was low in human U87 MG glioma, similar to that of ABT263, where Goss exerted sufficient cytotoxicity, suggesting that Hyp acts primarily on Bcl-2, but not on Mcl-1 protein. In combination therapy, low doses of Hyp with Goss effectively decreased U87 MG viability, suggesting a possible synergy effect. Overall, we can conclude that Hyp as BH3 mimetic acts primarily on Bcl-2 protein and can be explored to target cells with Bcl-2 over-expression, or in combination with other BH3 mimetics, that target Mcl-1 or Bcl-XL proteins, in dual therapy.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 94%

Hypericin, a potential new BH3 mimetic

et al. 2022

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“…Hypericin is one of the strongest photosensitizers in nature and is a dianthraquinone compound. Its specific targets are sites of tumor necrotic lesions . Delcanale et al showed that hypericin can self-assemble with apomyoglobin to form nanostructures.…”

Section: Applications Of Natural Phytochemical-based Nanostructuresmentioning

confidence: 99%

“…Its specific targets are of tumor necrotic lesions. 175 Delcanale et al 172 showed that hypericin can self-assemble with apomyoglobin to form nanostructures. In this self-assembled nanostructure, apomyoglobin can effectively improve the bioavailability and preserve the fluorescence and bacterial photoinactivation ability of hypericin.…”

Section: Applications Of Naturalmentioning

confidence: 99%

Review of Natural Phytochemical-Based Self-Assembled Nanostructures for Applications in Medicine

Zhu

Zhang

Wang

et al. 2022

ACS Appl. Nano Mater.

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The role of nanomedicine in disease diagnosis and treatment is indispensable. The future of nanomedicine in the pharmaceutical field is promising owing to its specificity and potency. However, its function and ultimate efficiency in clinical applications are still unsatisfactory, which can be attributed to the toxicity of nanomaterials caused by their nondegradability and accumulation in the body. To overcome the obstacles associated with the synthesized materials, researchers have focused on natural phytochemicals with good biodegradability, biocompatibility, and self-assembly capability. The structural diversity and combinational therapeutic effects of natural phytochemicals have broadened their nanomedical applications. This Review summarizes natural phytochemical-based nanostructures, including steroids, terpenoids, alkaloids, flavonoids, quinones, and polysaccharides and highlights their enormous application potential in nanomedicines. Additionally, in this Review, we summarize recent advances in nanostructures based on natural phytochemicals and introduce representative examples for drug-delivery, imaging, and theranostic applications in nanomedicine. Finally, we discuss the challenges in the rational design, synthesis, and fabrication of natural phytochemical-based nanostructures and propose feasible solutions for problems that need to be overcome to enable clinical translation.

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“…We have previously reported that the protein kinase C (PKC) signaling pathway is involved in the apoptotic response of glioblastoma cells to hypericin-mediated PDT [ 16 , 17 , 18 ]. We also observed the activation of PKCα and phosphorylation of Bcl2 in U87 MG glioblastoma cells after hypericin-mediated PDT [ 17 , 19 ]. The subcellular localizations of hypericin have been identified: the Golgi apparatus, lysosomes, plasma membrane and, in a few reports, in mitochondria [ 16 , 20 , 21 , 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Autophagy and Apoptosis Induced in U87 MG Glioblastoma Cells by Hypericin-Mediated Photodynamic Therapy Can Be Photobiomodulated with 808 nm Light

2021

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Glioblastoma is one of the most aggressive types of tumors. Although few treatment options are currently available, new modalities are needed to improve prognosis. In this context, photodynamic therapy (PDT) is a promising adjuvant treatment modality. In the present work, hypericin-mediated PDT (hypericin-PDT, 2 J/cm2) of U87 MG cells is combined with (2 min, 15 mW/cm2 at 808 nm) photobiomodulation (PBM). We observed that PBM stimulates autophagy, which, in combination with PDT, increases the treatment efficacy and leads to apoptosis. Confocal fluorescence microscopy, cytotoxicity assays and Western blot were used to monitor apoptotic and autophagic processes in these cells. Destabilization of lysosomes, mitochondria and the Golgi apparatus led to an increase in lactate dehydrogenase activity, oxidative stress levels, LC3-II, and caspase-3, as well as a decrease of the PKCα and STAT3 protein levels in response to hypericin-PDT subcellular concentration in U87 MG cells. Our results indicate that therapeutic hypericin concentrations can be reduced when PDT is combined with PBM. This will likely allow to reduce the damage induced in surrounding healthy tissues when PBM-hypericin-PDT is used for in vivo tumor treatments.

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Importance of Hypericin-Bcl2 interactions for biological effects at subcellular levels

Cited by 8 publications

References 112 publications

Hypericin, a potential new BH3 mimetic

Hypericin, a potential new BH3 mimetic

Review of Natural Phytochemical-Based Self-Assembled Nanostructures for Applications in Medicine

Autophagy and Apoptosis Induced in U87 MG Glioblastoma Cells by Hypericin-Mediated Photodynamic Therapy Can Be Photobiomodulated with 808 nm Light

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