Effect of licorice flavonoids as CDK1 inhibitors against liver cancer in vitro and in vivo

This study aimed to study the inhibitory activities of flavonoids on cell cycle-dependent protein kinase(CDK1)and hepatoma cells BEL-7402. The CDK1 inhibitory activity of licorice flavonoids was evaluated by CDK1 reagent kit, and antiproliferaty activity in vitro was investgated by CCK-8 assay. Subcutaneous tumor model of liver cancer Bel-7402 was established in nude mice, which were then randomly divided into drug group, positive drug group and blank control group. The mice in drug group were orally administrated with licorice flavonoids for continuous 18 days. The body weight and tumor size of mice were recorded every other day. The results demonstrated that these licorice flavonoids displayed potent efficacy against CDK1, specifically, isoliquiritigenin exhibited the most potent CDK1 inhibitory activity(IC₅₀=0. 05±0. 005 μmol/L), which was about 6-fold more potent than positive control flavopiridol(IC₅₀=0. 29±0. 230 μmol/L). Molecular docking studies revealed that isoliquiritigenin engaged in six hydrogen bonds with K33, E81, L83, S84, D86, D149 in CDK1, while flavopiridol only engaged in five hydrogen bonds with E81, L83, S84, Q132, D149. In vitro biological evaluation indicated that these licorice flavonoids displayed significant antiproliferative effects on Bel-7402 cancer cells. Among them, isoliquiritigenin showed the greatest potency against Bel-7402(IC₅₀=0. 7±0. 11 mol/L), which was 3-fold more potent than flavopiridol(2. 4±0. 34 mol/L). In vivo biological evaluation showed that the LD₅₀ of isoliquiritigenin was 4. 38 mg/kg, and could effectively inhibit the cell growth of liver cancer Bel-7402 in mice.