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

0532776 - MBÚ 2021 RIV CH eng J - Článek v odborném periodiku
Dobiasová, S. - Řehořová, K. - Kučerová, D. - Biedermann, David - Káňová, Kristýna - Petrásková, Lucie - Koucká, K. - Václavíková, R. - Valentová, Kateřina - Ruml, T. - Macek, T. - Křen, Vladimír - Viktorová, J.
Multidrug Resistance Modulation Activity of Silybin Derivatives and Their Anti-Inflammatory Potential.
Antioxidants. Roč. 9, č. 5 (2020), č. článku 455. E-ISSN 2076-3921
Grant CEP: GA ČR(CZ) GA18-00150S
Institucionální podpora: RVO:61388971
Klíčová slova: silybin * dehydrosilybin * immunomodulation * P-glycoprotein * doxorubicin resistance,
Obor OECD: Medicinal chemistry
Impakt faktor: 6.313, rok: 2020
Způsob publikování: Open access
https://www.mdpi.com/2076-3921/9/5/455

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.
Trvalý link: http://hdl.handle.net/11104/0311240