Development of Biaryl-Containing Aldo-Keto Reductase 1C3 (AKR1C3) Inhibitors for Reversing AKR1C3-Mediated Drug Resistance in Cancer Treatment

Abstract

Aldo-keto reductase 1C3 (AKR1C3) is correlated with tumor development and chemotherapy resistance. The catalytic activity of the enzyme has been recognized as one of the important factors in inducing anthracycline (ANT) resistance in cancer cells. Inhibition of AKR1C3 activity may provide a promising approach to restore the chemosensitivity of ANT-resistant cancers. Herein, a series of biaryl-containing AKR1C3 inhibitors has been developed. The best analogue S07-1066 selectively blocked AKR1C3-mediated reduction of doxorubicin (DOX) in MCF-7 transfected cell models. Furthermore, co-treatment of S07-1066 significantly synergized DOX cytotoxicity and reversed the DOX resistance in MCF-7 cells overexpressing AKR1C3. The potential synergism of S07-1066 over DOX cytotoxicity was demonstrated in vitro and in vivo. Our findings indicate that inhibition of AKR1C3 potentially enhances the therapeutic efficacy of ANTs and even suggests that AKR1C3 inhibitors may serve as effective adjuvants to overcome AKR1C3-mediated chemotherapy resistance in cancer treatment.

AKR1C3 promotes progression and mediates therapeutic resistance by inducing epithelial-mesenchymal transition and angiogenesis in small cell lung cancer

“…AKRs have been found to be upregulated in various cancers, including prostate cancer [ 6 ], hepatocellular carcinoma [ 7 ], breast cancer [ 8 ], non-small-cell lung cancer (NSCLC) [ 9 ] and SCLC [ 10 ]. Notably, AKR1C3 has been reported to be closely associated with the prognosis of different tumors and clinical drug resistance [ [11] , [12] , [13] , [14] ]. Previous study has shown that AKR1C3 promoted hepatocellular carcinoma cell proliferation and invasion through the IL6/STAT3 pathway by regulating NF-κB activity [ 15 ].…”