Мақола

Multidrug Resistance Modulation Activity of Silybin Derivatives and Their Anti-Inflammatory Potential

Simona DobiasováDepartment of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technická 5, CZ 166 28 Prague, Czech RepublicKateřina ŘehořováDepartment of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technická 5, CZ 166 28 Prague, Czech RepublicDenisa KučerováDepartment of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technická 5, CZ 166 28 Prague, Czech RepublicDavid BiedermannLaboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ 142 20 Prague, Czech RepublicKristýna KáňováDepartment of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technická 5, CZ 166 28 Prague, Czech RepublicLucie PetráskováLaboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ 142 20 Prague, Czech RepublicKamila KouckáLaboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655, CZ 323 00 Pilsen, Czech RepublicRadka VáclavíkováLaboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1655, CZ 323 00 Pilsen, Czech RepublicKateřina ValentováLaboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ 142 20 Prague, Czech RepublicTomáš RumlDepartment of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technická 5, CZ 166 28 Prague, Czech RepublicTomáš MacekDepartment of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technická 5, CZ 166 28 Prague, Czech RepublicVladimı́r KřenLaboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ 142 20 Prague, Czech RepublicJitka ViktorováDepartment of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technická 5, CZ 166 28 Prague, Czech Republic

2020en

ABI

Аннотация

Silybin is considered to be the main biologically active component of silymarin. Its oxidized derivative 2,3-dehydrosilybin typically occurs in silymarin in small, but non-negligible amounts (up to 3%). Here, we investigated in detail complex biological activities of silybin and 2,3-dehydrosilybin optical isomers. Antioxidant activities of pure stereomers A and B of silybin and 2,3-dehydrosilybin, as well as their racemic mixtures, were investigated by using oxygen radical absorption capacity (ORAC) and cellular antioxidant activity (CAA) assay. All substances efficiently reduced nitric oxide production and cytokines (TNF-α, IL-6) release in a dose-dependent manner. Multidrug resistance (MDR) modulating potential was evaluated as inhibition of P-glycoprotein (P-gp) ATPase activity and regulation of ATP-binding cassette (ABC) protein expression. All the tested compounds showed strong dose-dependent inhibition of P-gp pump. Moreover, 2,3-dehydrosilybin A (30 µM) displayed the strongest sensitization of doxorubicin-resistant ovarian carcinoma. Despite these significant effects, silybin B was the only compound acting directly upon P-gp in vitro and also downregulating the expression of respective MDR genes. This compound altered the expression of P-glycoprotein (P-gp, ABCB1), multidrug resistance-associated protein 1 (MRP1, ABCC1) and breast cancer resistance protein (BCRP, ABCG2). 2,3-Dehydrosilybin AB exhibited the most effective inhibition of acetylcholinesterase activity. We can clearly postulate that silybin derivatives could serve well as modulators of a cancer drug-resistant phenotype.

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Идентификаторлар

DOI: 10.3390/antiox9050455

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