Trans-(±)-kusunokinin suppresses AKR1B1: inhibition of oxidative stress and alteration of epithelial-mesenchymal transition markers on aggressive cancer

Background: Trans-(-)-kusunokinin, a multi-target molecule (such as CSF1R, MMP-12, HSP90-α, cyclinB1, MEK1, HER2 and AKR1B1), inhibited breast, cholangiocarcinoma, colon ovarian cancer cells proliferation. In addition, natural trans-(−)-kusunokinin inhibits tumor growth migration in the rat model. However, there is no evidence to confirm interaction effects of synthetic trans-(±)-kusunokinin (KU) against AKR1B1. this work, we investigated action AKR1B1 enzyme activity consequently suppression its downstream molecules. Material methods: The inhibition aldose-reductase by KU was determined using an aldose reductase inhibitor screening kit. Intracellular activities including cytotoxicity, drug-target oxidative stress were MTT, CETSA TBARS assays, respectively. MTT assay performed on breast (BT549, Hs578 T MCF7) (A2780, SKOV3 OVCAR3) cells. done high expression (Hs578 SKOV3). treated with KU, known (epalrestat (EP)) siRNA-AKR1B1 for 48 hrs. Finally, molecules measured Western blotting. Results: IC50 value 9.72 ± 0.18 μM less effectiveness than EP (0.77 0.01 μM). exhibited strongest cytotoxicity which stronger zopolrestat, cisplatin. Interestingly, stabilized at 60°C 75°C dose-dependence manner. also lipid peroxidation Moreover, showed ROS EP. AKRIB1 represented down-regulation proteins (PKC-δ, NF-kB, AKT, STAT3, Nrf2, COX2, Twist2 N-cadherin). Nevertheless, E-cadherin up-regulated during treatment. Conclusions: conclusion, binding caused activity, cellular aggressive cancer. No conflict interest.