Carbonyl reductase 1 as a novel target of (−)‐epigallocatechin gallate against hepatocellular carcinoma†

Abstract

Human carbonyl reductase 1 (CBR1) converts the antitumor drug and anthracycline daunorubicin (DNR) into the alcohol metabolite daunorubicinol (DNROL) with significantly reduced antitumor activity and cardiotoxicity, and this limits the clinical use of DNR. Inhibition of CBR1 can thus increase the efficacy and decrease the toxicity of DNR. Here we report that (-)-epigallocatechin gallate (EGCG) from green tea is a promising inhibitor of CBR1. EGCG directly interacts with CBR1 and acts as a noncompetitive inhibitor with respect to the cofactor reduced nicotinamide adenine dinucleotide phosphate and the substrate isatin. The inhibition is dependent on the pH, and the gallate moiety of EGCG is required for activity. Molecular modeling has revealed that EGCG occupies the active site of CBR1. Furthermore, EGCG specifically enhanced the antitumor activity of DNR against hepatocellular carcinoma SMMC7721 cells expressing high levels of CBR1 and corresponding xenografts. We also demonstrated that EGCG could overcome the resistance to DNR by Hep3B cells stably expressing CBR1 but not by RNA interference of CBR1-HepG2 cells. The level of the metabolite DNROL was negatively correlated with that of EGCG in the cell extracts. Finally, EGCG decreased the cardiotoxicity of DNR in a human carcinoma xenograft model with both SMMC7721 and Hep3B cells in mice. These results strongly suggest that EGCG can inhibit CBR1 activity and enhance the effectiveness and decrease the cardiotoxicity of the anticancer drug DNR. These findings also indicate that a combination of EGCG and DNR might represent a novel approach for hepatocellular carcinoma therapy or chemoprevention.