Antioxidant, Anti-Inflammatory, and Multidrug Resistance Modulation Activity of Silychristin Derivatives

• Main Authors: Jitka Viktorová, Simona Dobiasová, Kateřina Řehořová, David Biedermann, Kristýna Káňová, Karolína Šeborová, Radka Václavíková, Kateřina Valentová, Tomáš Ruml, Vladimír Křen, Tomáš Macek
• Format: Article
• Language: English
• Published: MDPI AG 2019-08-01
• Series: Antioxidants
• Subjects: Adriamycin; P-glycoprotein; silymarin; silychristin; immunomodulation; ABC superfamily; BCRP; expression profile
• Online Access: https://www.mdpi.com/2076-3921/8/8/303

Silychristin A is the second most abundant compound of silymarin. Silymarin complex was previously described as an antioxidant with multidrug resistance modulation activity. Here, the results of a classical biochemical antioxidant assay (ORAC) were compared with a cellular assay evaluating the antioxidant capacity of pure silychristin A and its derivatives (anhydrosilychristin, isosilychristin and 2,3-dehydrosilychristin A). All the tested compounds acted as antioxidants within the cells, but 2,3-dehydro- and anhydro derivatives were almost twice as potent as the other tested compounds. Similar results were obtained in LPS-stimulated macrophages, where 2,3-dehydro- and anhydrosilychristin inhibited NO production nearly twice as efficiently as silychristin A. The inhibition of P-glycoprotein (P-gp) was determined in vitro, and the respective sensitization of doxorubicin-resistant ovarian carcinoma overproducing P-gp was detected. Despite the fact that the inhibition of P-gp was demonstrated in a concentration-dependent manner for each tested compound, the sensitization of the resistant cell line was observed predominantly for silychristin A and 2,3-dehydrosilychristin A. However, anhydrosilychristin and isosilychristin affected the expression of both the P-gp (<i>ABCB1</i>) and <i>ABCG2</i> genes. This is the first report showing that silychristin A and its 2,3-dehydro-derivative modulate multidrug resistance by the direct inhibition of P-gp, in contrast to anhydrosilychristin and isosilychristin modulating multidrug resistance by downregulating the expression of the dominant transmembrane efflux pumps.