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
Department of Biochemistry and Microbiology, University of Chemistry and Technology Prague, Technická 5, CZ 166 28 Prague, Czech Republic.
Laboratory of Biotransformation, Institute of Microbiology of the Czech Academy of Sciences, Vídeňská 1083, CZ 142 20 Prague, Czech Republic.
Antioxidants (Basel). 2020 May 25;9(5):455. 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.
水飞蓟宾被认为是水飞蓟素的主要生物活性成分。其氧化衍生物2,3 - 脱氢水飞蓟宾在水飞蓟素中含量虽少，但不可忽略（高达3%）。在此，我们详细研究了水飞蓟宾和2,3 - 脱氢水飞蓟宾光学异构体的复杂生物活性。通过氧自由基吸收能力（ORAC）和细胞抗氧化活性（CAA）测定法，研究了水飞蓟宾和2,3 - 脱氢水飞蓟宾的纯立体异构体A和B及其外消旋混合物的抗氧化活性。所有物质均以剂量依赖性方式有效降低一氧化氮生成和细胞因子（TNF-α、IL-6）释放。通过抑制P - 糖蛋白（P-gp）ATP酶活性和调节ATP结合盒（ABC）蛋白表达来评估多药耐药（MDR）调节潜力。所有测试化合物均表现出对P - gp泵的强烈剂量依赖性抑制作用。此外，2,3 - 脱氢水飞蓟宾A（30 μM）对多柔比星耐药的卵巢癌表现出最强的增敏作用。尽管有这些显著效果，但水飞蓟宾B是唯一在体外直接作用于P - gp并下调相应MDR基因表达的化合物。该化合物改变了P - 糖蛋白（P-gp）、多药耐药相关蛋白1（MRP1）和乳腺癌耐药蛋白（BCRP）的表达。2,3 - 脱氢水飞蓟宾AB对乙酰胆碱酯酶活性表现出最有效的抑制作用。我们可以明确推测，水飞蓟宾衍生物可很好地作为癌症耐药表型的调节剂。
