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

Abstract

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.

Comparison of Chemical Composition and Biological Activities of Eight Selaginella Species

“…The Ellman colorimetric method [ 68 ] was used to measure the activity of acetylcholinesterase (AChE). The crude extracts were analyzed using binary dilution in the concentration range of 62.5–0.125 mg/L.…”

Systematic review of pharmacokinetics and potential pharmacokinetic interactions of flavonolignans from silymarin

“…P‐glycoprotein does not seem to be very sensitive for inhibition by silymarin or silybin, similarly to other known efflux transporters BCRP and MRP‐1. On the other hand, racemic 2,3‐dehydrosilybin, silychristin A, 2,3‐dehydrosilychristin A, isosilychristin, and anhydrosilychristin had an IC 50 on P‐glycoprotein in the range of 15–26 µM 15,226 . Some organic anion transporting polypeptides (OATP) can be blocked with units of micromolar or even hundreds of nM.…”

“…Since that time, several other studies have analyzed the effect of silymarin or silybin on the expression of cytochrome P450 and P‐glycoprotein 192–195,198,203,230 . Recent studies also showed that anhydrosilychristin and silybin B can substantially decrease the expression of P‐glycoprotein and BCRP, but silybin A, 2,3‐dehydrosilybin (A, B, racemate), and silychristin A had no effect, while 2,3‐dehydrosilychristin only decreased the expression of BCRP 15,226 . A decrease in BCRP expression was also reported previously after treatment with silymarin 220 .…”

Evaluation of silibinin as an efflux pump inhibitor in Bacillus subtilis

“…Silibinin (or silybin) is the major component of silymarin extract from the seeds of Silybum marianum (or milk thistle, Asteraceae) and a member of flavonolignans. (Dobiasová et al, 2020). It receives wide attention due to its anticancer, antioxidant, antibacterial, antifungal, antiinflammatory, cardioprotective, neuroprotective, and hepatoprotective activities (de Oliveira et al, 2015;Shen et al, 2018;Wlcek et al, 2013).…”