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Article: Multifunctional Nanoplatforms as a Novel Effective Approach in Photodynamic Therapy and Chemotherapy, to Overcome Multidrug Resistance in Cancer.

Majerník, Martin / Jendželovský, Rastislav / Vargová, Jana / Jendželovská, Zuzana / Fedoročko, Peter

2022 Volume 14, Issue 5

Abstract: It is more than sixty years since the era of modern photodynamic therapy (PDT) for cancer began. Enhanced selectivity for malignant cells with a reduced selectivity for non-malignant cells and good biocompatibility along with the limited occurrence of ... ...

Abstract	It is more than sixty years since the era of modern photodynamic therapy (PDT) for cancer began. Enhanced selectivity for malignant cells with a reduced selectivity for non-malignant cells and good biocompatibility along with the limited occurrence of side effects are considered to be the most significant advantages of PDT in comparison with conventional therapeutic approaches, e.g., chemotherapy. The phenomenon of multidrug resistance, which is associated with drug efflux transporters, was originally identified in relation to the application of chemotherapy. Unfortunately, over the last thirty years, numerous papers have shown that many photosensitizers are the substrates of efflux transporters, significantly restricting the effectiveness of PDT. The concept of a dynamic nanoplatform offers a possible solution to minimize the multidrug resistance effect in cells affected by PDT. Indeed, recent findings have shown that the utilization of nanoparticles could significantly enhance the therapeutic efficacy of PDT. Additionally, multifunctional nanoplatforms could induce the synergistic effect of combined treatment regimens, such as PDT with chemotherapy. Moreover, the surface modifications that are associated with nanoparticle functionalization significantly improve the target potential of PDT or chemo-PDT in multidrug resistant and cancer stem cells.
Language	English
Publishing date	2022-05-17
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics14051075
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Article: Potentiality, Limitations, and Consequences of Different Experimental Models to Improve Photodynamic Therapy for Cancer Treatment in Relation to Antiangiogenic Mechanism.

Majerník, Martin / Jendželovský, Rastislav / Fedoročko, Peter

Cancers

2020 Volume 12, Issue 8

Abstract: The relevance of experimentally gained information represents a long-term debating issue in the field of molecular biology research. The loss of original conditions in the in vitro environment affects various biological mechanisms and cellular ... ...

Abstract	The relevance of experimentally gained information represents a long-term debating issue in the field of molecular biology research. The loss of original conditions in the in vitro environment affects various biological mechanisms and cellular interactions. Consequently, some biochemical mechanisms are lost or critically altered. Analyses in these modified conditions could, therefore, distort the relevancy of experimentally gained information. In some cases, the similarities with original conditions are so small that utilization of simpler in vitro models seems impossible, or could occur in a very limited way. To conclude, the study of more complex phenomena places higher demands on the complexity of the experimental model. The latest information highlights the fact that the tumor angiogenesis mechanism has very complex features. This complexity can be associated with a wide range of angiogenic factors expressed by a variety of malignant and non-malignant cells. Our article summarizes the results from various experimental models that were utilized to analyze a photodynamic therapy effect on tumor angiogenic mechanisms. Additionally, based on the latest information, we present the most important attributes and limitations of utilized experimental models. We also evaluate the essential problems associated with angiogenic mechanism induction after photodynamic therapy application.
Language	English
Publishing date	2020-07-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12082118
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Article ; Online: New findings on the action of hypericin in hypoxic cancer cells with a focus on the modulation of side population cells.

Buľková, Viktória / Vargová, Jana / Babinčák, Marián / Jendželovský, Rastislav / Zdráhal, Zbyněk / Roudnický, Pavel / Košuth, Ján / Fedoročko, Peter

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2023 Volume 163, Page(s) 114829

Abstract: The presence of key hypoxia regulators, namely, hypoxia-inducible factor (HIF)-1α or HIF-2α, in tumors is associated with poor patient prognosis. Hypoxia massively activates several genes, including the one encoding the BCRP transporter that proffers ... ...

Abstract	The presence of key hypoxia regulators, namely, hypoxia-inducible factor (HIF)-1α or HIF-2α, in tumors is associated with poor patient prognosis. Hypoxia massively activates several genes, including the one encoding the BCRP transporter that proffers multidrug resistance to cancer cells through the xenobiotic efflux and is a determinant of the side population (SP) associated with cancer stem-like phenotypes. As natural medicine comes to the fore, it is instinctive to look for natural agents possessing powerful features against cancer resistance. Hypericin, a pleiotropic agent found in Hypericum plants, is a good example as it is a BCRP substrate and potential inhibitor, and an SP and HIF modulator. Here, we showed that hypericin efficiently accumulated in hypoxic cancer cells, degraded HIF-1/2α, and decreased BCRP efflux together with hypoxia, thus diminishing the SP population. On the contrary, this seemingly favorable result was accompanied by the stimulated migration of this minor population that preserved the SP phenotype. Because hypoxia unexpectedly decreased the BCRP level and SP fraction, we compared the SP and non-SP proteomes and their changes under hypoxia in the A549 cell line. We identified differences among protein groups connected to the epithelial-mesenchymal transition, although major changes were related to hypoxia, as the upregulation of many proteins, including serpin E1, PLOD2 and LOXL2, that ultimately contribute to the initiation of the metastatic cascade was detected. Altogether, this study helps in clarifying the innate and hypoxia-triggered resistance of cancer cells and highlights the ambivalent role of natural agents in the biology of these cells.
MeSH term(s)	Humans ; Side-Population Cells/pathology ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics ; ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Hypoxia ; Neoplasms/metabolism ; Cell Hypoxia ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Cell Line, Tumor ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Gene Expression Regulation, Neoplastic
Chemical Substances	hypericin (7V2F1075HD) ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Neoplasm Proteins ; Hypoxia-Inducible Factor 1, alpha Subunit ; Basic Helix-Loop-Helix Transcription Factors
Language	English
Publishing date	2023-05-03
Publishing country	France
Document type	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2023.114829
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Article ; Online: The potential of hypericin and hyperforin for antiadhesion therapy to prevent metastasis of parental and oxaliplatin-resistant human adenocarcinoma cells (HT-29).

Šemeláková, Martina / Sačková, Veronika / Fedoročko, Peter

Anti-cancer drugs

2018 Volume 29, Issue 10, Page(s) 983–994

Abstract: Cancer cells disseminate to other parts of the body during metastasis through the process of intravasation. The hypericin and hyperforin effect has been described to understand the signal mechanisms that stimulate or stunt cancer cell sprouting to ... ...

Abstract	Cancer cells disseminate to other parts of the body during metastasis through the process of intravasation. The hypericin and hyperforin effect has been described to understand the signal mechanisms that stimulate or stunt cancer cell sprouting to metastasis on colon adenocarcinoma cells HT-29 and its resistant form HT-29-OxR. We focused on the key points of adhesion proteins (cadherin, integrin, selectin and syndecan) and also proteins participating in or contributing to the process of cancer cell migration and adhesion through genes expression and proteins levels. Treatment effects were identified as a consequence of decreased cell adhesion, changes of expression in the adhesive proteins as well as basal membrane degradation associated with changes in the expression of matrix proteinases and in their activity. Finally, the cells affected by hypericin or hyperforin were evaluated by monitoring the cancer cell adhesion properties and proliferation processes. Supplementary Fig. (Supplemental digital content 1, http://links.lww.com/ACD/A267).
MeSH term(s)	Adenocarcinoma/drug therapy ; Adenocarcinoma/pathology ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Cell Adhesion/drug effects ; Cell Movement/drug effects ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/pathology ; Drug Resistance, Neoplasm ; HT29 Cells ; Humans ; Neoplasm Metastasis/prevention & control ; Oxaliplatin/administration & dosage ; Oxaliplatin/pharmacology ; Perylene/administration & dosage ; Perylene/analogs & derivatives ; Perylene/pharmacology ; Phloroglucinol/administration & dosage ; Phloroglucinol/analogs & derivatives ; Phloroglucinol/pharmacology ; Terpenes/administration & dosage ; Terpenes/pharmacology
Chemical Substances	Terpenes ; Oxaliplatin (04ZR38536J) ; Perylene (5QD5427UN7) ; hypericin (7V2F1075HD) ; Phloroglucinol (DHD7FFG6YS) ; hyperforin (RM741E34FP)
Language	English
Publishing date	2018-07-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1065301-6
ISSN	1473-5741 ; 0959-4973
ISSN (online)	1473-5741
ISSN	0959-4973
DOI	10.1097/CAD.0000000000000676
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Article ; Online: Breast cancer resistance protein is the enemy of hypericin accumulation and toxicity of hypericin-mediated photodynamic therapy.

Jendželovský, Rastislav / Jendželovská, Zuzana / Kuchárová, Barbora / Fedoročko, Peter

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2018 Volume 109, Page(s) 2173–2181

Abstract: Breast cancer resistance protein (BCRP) belongs to the family of ATP-binding cassette (ABC) transporters, overexpression of which can confer a multidrug-resistant phenotype in cancer cells and tumors. BCRP mediates efflux of numerous xenobiotics, ... ...

Abstract	Breast cancer resistance protein (BCRP) belongs to the family of ATP-binding cassette (ABC) transporters, overexpression of which can confer a multidrug-resistant phenotype in cancer cells and tumors. BCRP mediates efflux of numerous xenobiotics, including various chemotherapeutic agents and photosensitizers. Hypericin (HY) is a naturally-occurring photosensitizer synthesized by plants of the genus Hypericum. Our recently published results indicate that accumulation of HY in cancer cells of different tissue origin can be affected mostly by BCRP. Considering all known facts, the main goal of this study was to verify whether not only HY accumulation but also toxicity of HY-mediated photodynamic therapy (PDT) can be affected by the presence of some ABC transporters. To specifically prove our hypothesis, we used an experimental model of human leukemia cell lines differing in the expression level of the main drug efflux transporters P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and BCRP. The lowest HY accumulation, and consequently the highest resistance to HY-PDT, was found in cells overexpressing BCRP. Moreover, pretreatment with BCRP inhibitor Ko143 significantly increased HY accumulation and sensitized cells to HY-PDT. Therefore, our findings represent direct evidence that BCRP is the nemesis of HY accumulation and toxicity of HY-PDT. Thus, we should emphasize that individualized screening for BCRP expression and activity may represent a useful tool for prediction of HY-mediated photodynamic diagnosis (PDD) or PDT effectiveness.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; Antineoplastic Agents/metabolism ; Antineoplastic Agents/toxicity ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Breast Neoplasms/radiotherapy ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/physiology ; Female ; HL-60 Cells ; Humans ; Neoplasm Proteins/metabolism ; Perylene/analogs & derivatives ; Perylene/antagonists & inhibitors ; Perylene/metabolism ; Perylene/toxicity ; Photochemotherapy/adverse effects ; Radiation-Sensitizing Agents/metabolism ; Radiation-Sensitizing Agents/toxicity
Chemical Substances	ABCG2 protein, human ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Antineoplastic Agents ; Neoplasm Proteins ; Radiation-Sensitizing Agents ; Perylene (5QD5427UN7) ; hypericin (7V2F1075HD)
Language	English
Publishing date	2018-11-27
Publishing country	France
Document type	Journal Article
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2018.11.084
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Article ; Online: Acridine Based

Vilková, Mária / Hudáčová, Monika / Palušeková, Nikola / Jendželovský, Rastislav / Almáši, Miroslav / Béres, Tibor / Fedoročko, Peter / Kožurková, Mária

Molecules (Basel, Switzerland)

2022 Volume 27, Issue 9

Abstract: A series of novel acridine N-acylhydrazone derivatives have been synthesized as potential topoisomerase I/II inhibitors, and their binding (calf thymus DNA—ctDNA and human serum albumin—HSA) and biological activities as potential anticancer agents on ... ...

Abstract	A series of novel acridine N-acylhydrazone derivatives have been synthesized as potential topoisomerase I/II inhibitors, and their binding (calf thymus DNA—ctDNA and human serum albumin—HSA) and biological activities as potential anticancer agents on proliferation of A549 and CCD-18Co have been evaluated. The acridine-DNA complex 3b (-F) displayed the highest Kb value (Kb = 3.18 × 103 M−1). The HSA-derivatives interactions were studied by fluorescence quenching spectra. This method was used for the calculation of characteristic binding parameters. In the presence of warfarin, the binding constant values were found to decrease (KSV = 2.26 M−1, Kb = 2.54 M−1), suggesting that derivative 3a could bind to HSA at Sudlow site I. The effect of tested derivatives on metabolic activity of A549 cells evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide or MTT assay decreased as follows 3b(-F) > 3a(-H) > 3c(-Cl) > 3d(-Br). The derivatives 3c and 3d in vitro act as potential dual inhibitors of hTopo I and II with a partial effect on the metabolic activity of cancer cells A594. The acridine-benzohydrazides 3a and 3c reduced the clonogenic ability of A549 cells by 72% or 74%, respectively. The general results of the study suggest that the novel compounds show potential for future development as anticancer agents.
MeSH term(s)	Acridines/chemistry ; Antineoplastic Agents/chemistry ; Binding Sites ; Humans ; Intercalating Agents ; Serum Albumin, Human/chemistry ; Topoisomerase II Inhibitors/pharmacology
Chemical Substances	Acridines ; Antineoplastic Agents ; Intercalating Agents ; Topoisomerase II Inhibitors ; Serum Albumin, Human (ZIF514RVZR)
Language	English
Publishing date	2022-04-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules27092883
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Article ; Online: In vitro study of disodium cromoglicate as a novel effective hydrotrope solvent for hypericin utilisation in photodynamic therapy.

Suváková, Mária / Majerník, Martin / Jendželovský, Rastislav / Hovan, Andrej / Bánó, Gregor / Fedoročko, Peter / Antalík, Marián

Journal of photochemistry and photobiology. B, Biology

2020 Volume 206, Page(s) 111855

Abstract: Hypericin (HY) is a naphthodianthrone that naturally occurs in Hypericum perforatum L. It is a promising photosensitiser used in photodynamic therapy for and diagnosis of oncological diseases. However, its hydrophobic character is an obstacle that has ... ...

Abstract	Hypericin (HY) is a naphthodianthrone that naturally occurs in Hypericum perforatum L. It is a promising photosensitiser used in photodynamic therapy for and diagnosis of oncological diseases. However, its hydrophobic character is an obstacle that has prevented its efficient use. The commonly used solvent, dimethyl sulfoxide (DMSO), is a controversial constituent of HY formulations and its use has been rejected by many researchers studying HY both in vitro and in vivo. In this study, we propose the utilisation of hydrotropy to solubilise HY in an aqueous environment. Cromolyn (DSCG) is a non-toxic, well-tolerated, antiallergic drug that has been employed in clinical practice since 1970, and in aqueous solution it acts as a hydrotrope. At a molecular ratio of 1:12,000 HY to DSCG, the compound is able to solubilise HY in aqueous environment. In an HT-29 cell suspension, DSCG (1.8 mmol L
Language	English
Publishing date	2020-03-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	623022-2
ISSN	1873-2682 ; 1011-1344
ISSN (online)	1873-2682
ISSN	1011-1344
DOI	10.1016/j.jphotobiol.2020.111855
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Zs.A 2347: Show issues

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Article ; Online: Combination of photoactive hypericin and Manumycin A exerts multiple anticancer effects on oxaliplatin-resistant colorectal cells.

Macejová, Mária / Sačková, Veronika / Hradická, Petra / Jendželovský, Rastislav / Demečková, Vlasta / Fedoročko, Peter

Toxicology in vitro : an international journal published in association with BIBRA

2020 Volume 66, Page(s) 104860

Abstract: The use of natural products as chemotherapeutic agents and tools for manipulation of apoptosis represent an attractive therapeutic concept. In this study, we investigated the anticancer activities of a combination of two natural compounds with different ... ...

Abstract	The use of natural products as chemotherapeutic agents and tools for manipulation of apoptosis represent an attractive therapeutic concept. In this study, we investigated the anticancer activities of a combination of two natural compounds with different origin, hypericin (plant product) in its photoactive state and Manumycin A (yeast product) and explored the underlying mechanisms of their pro-apoptotic action using an oxaliplatin-resistant variant of human colon adenocarcinoma cell line HT-29-OxR as the experimental model. CCK-8 assay was performed to evaluate the cytotoxicity of the drugs. CalcuSyn software was used to identify the type of interaction between the two agents. BrdU incorporation assay and colony forming assay were performed to study the short- and long-term proliferation of cells. To evaluate the ability of the drug combination to induce apoptosis, PARP p85 fragment was detected using the ELISA method. Changes in apoptosis-related proteins were examined by immunoassays. Our results showed that a synergistic combination of photoactive hypericin and Manumycin A decreased viability, inhibited both short- and long-term cell proliferation, decreased levels of IAPs proteins (cIAP1, cIAP2, XIAP and survivin), induced an apoptotic PARP cleavage associated with decline in procaspase-3 level, promoted phagocytosis of cancer cells, and restored chemosensitivity to oxaliplatin.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Antineoplastic Agents/radiation effects ; Apoptosis Regulatory Proteins/metabolism ; Cell Line ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/metabolism ; Drug Resistance, Neoplasm/drug effects ; Drug Synergism ; Humans ; Light ; Macrophages/drug effects ; Macrophages/physiology ; Oxaliplatin/pharmacology ; Perylene/analogs & derivatives ; Perylene/pharmacology ; Perylene/radiation effects ; Phagocytosis/drug effects ; Polyenes/pharmacology ; Polyunsaturated Alkamides/pharmacology
Chemical Substances	Antineoplastic Agents ; Apoptosis Regulatory Proteins ; Polyenes ; Polyunsaturated Alkamides ; Oxaliplatin (04ZR38536J) ; Perylene (5QD5427UN7) ; hypericin (7V2F1075HD) ; manumycin (OIQ298X4XD)
Language	English
Publishing date	2020-04-13
Publishing country	England
Document type	Journal Article
ZDB-ID	639064-x
ISSN	1879-3177 ; 0887-2333
ISSN (online)	1879-3177
ISSN	0887-2333
DOI	10.1016/j.tiv.2020.104860
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Zs.A 2223: Show issues

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Article: Death Receptor 5 (TNFRSF10B) Is Upregulated and TRAIL Resistance Is Reversed in Hypoxia and Normoxia in Colorectal Cancer Cell Lines after Treatment with Skyrin, the Active Metabolite of

Babinčák, Marián / Jendželovský, Rastislav / Košuth, Ján / Majerník, Martin / Vargová, Jana / Mikulášek, Kamil / Zdráhal, Zbyněk / Fedoročko, Peter

Cancers

2021 Volume 13, Issue 7

Abstract: Skyrin (SKR) is a plant bisanthraquinone secondary metabolite from ... ...

Abstract	Skyrin (SKR) is a plant bisanthraquinone secondary metabolite from the
Language	English
Publishing date	2021-04-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13071646
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Article ; Online: Tacrine-Coumarin Derivatives as Topoisomerase Inhibitors with Antitumor Effects on A549 Human Lung Carcinoma Cancer Cell Lines.

Konkoľová, Eva / Hudáčová, Monika / Hamuľaková, Slávka / Jendželovský, Rastislav / Vargová, Jana / Ševc, Juraj / Fedoročko, Peter / Kožurková, Mária

Molecules (Basel, Switzerland)

2021 Volume 26, Issue 4

Abstract: A549 human lung carcinoma cell lines were treated with a series of new drugs with both tacrine and coumarin pharmacophores ( ... ...

Abstract	A549 human lung carcinoma cell lines were treated with a series of new drugs with both tacrine and coumarin pharmacophores (derivatives
MeSH term(s)	A549 Cells ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Proliferation/drug effects ; Coumarins/chemistry ; Coumarins/pharmacology ; DNA Topoisomerases, Type I/metabolism ; DNA Topoisomerases, Type II/metabolism ; Drug Screening Assays, Antitumor ; Humans ; Molecular Structure ; Poly-ADP-Ribose Binding Proteins/antagonists & inhibitors ; Poly-ADP-Ribose Binding Proteins/metabolism ; Tacrine/chemistry ; Tacrine/pharmacology ; Topoisomerase I Inhibitors/chemistry ; Topoisomerase I Inhibitors/pharmacology ; Topoisomerase II Inhibitors/chemistry ; Topoisomerase II Inhibitors/pharmacology ; Tumor Cells, Cultured
Chemical Substances	Antineoplastic Agents ; Coumarins ; Poly-ADP-Ribose Binding Proteins ; Topoisomerase I Inhibitors ; Topoisomerase II Inhibitors ; Tacrine (4VX7YNB537) ; DNA Topoisomerases, Type I (EC 5.99.1.2) ; TOP1 protein, human (EC 5.99.1.2) ; DNA Topoisomerases, Type II (EC 5.99.1.3) ; TOP2A protein, human (EC 5.99.1.3)
Language	English
Publishing date	2021-02-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules26041133
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