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

• Published in: Antioxidants Vol. 9; no. 5; p. 455
• Main Authors: Dobiasová, Simona, Řehořová, Kateřina, Kučerová, Denisa, Biedermann, David, Káňová, Kristýna, Petrásková, Lucie, Koucká, Kamila, Václavíková, Radka, Valentová, Kateřina, Ruml, Tomáš, Macek, Tomáš, Křen, Vladimír, Viktorová, Jitka
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 25-05-2020; MDPI
• Subjects: Acetylcholinesterase; Adenosine triphosphatase; Anti-inflammatory agents; Antibiotics; Antioxidants; Biological activity; Breast cancer; Control; Cytokines; Cytotoxicity; Dehydrosilybin; Doxorubicin; doxorubicin resistance; Evaluation; Flavonoids; Growth factors; Health aspects; immunomodulation; Inflammation; Interleukin 6; Isomers; Lung cancer; Medicinal plants; Microbial drug resistance; Milk thistle; Mitochondrial DNA; Multidrug resistance; Nitric oxide; Ovarian cancer; Ovarian carcinoma; P-Glycoprotein; Phenotypes; silybin; Silymarin; Tumor necrosis factor-α; Czech Republic; United States > US; P-glycoprotein; immunomodulation; dehydrosilybin; silybin; acetylcholinesterase inhibition; cytokines; doxorubicin resistance; expression profile
• ISSN: 2076-3921; 2076-3921
• DOI: 10.3390/antiox9050455

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,
), multidrug resistance-associated protein 1 (MRP1,
) and breast cancer resistance protein (BCRP,
). 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.