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Merck
  • Reversal of Apalutamide and Darolutamide Aldo-Keto Reductase 1C3-Mediated Resistance by a Small Molecule Inhibitor.

Reversal of Apalutamide and Darolutamide Aldo-Keto Reductase 1C3-Mediated Resistance by a Small Molecule Inhibitor.

ACS chemical biology (2020-03-04)
Ahmed Morsy, Paul C Trippier
초록

The antiandrogen therapeutics apalutamide and darolutamide entered the clinic in 2018 and 2019, respectively, for the treatment of castration-resistant prostate cancer (CRPC). Increased expression of the enzyme aldo-keto reductase 1C3 (AKR1C3) is phenotypic of CRPC. The enzyme acts to circumvent castration by producing potent androgens that drive proliferation. Furthermore, AKR1C3 mediates chemotherapeutic resistance to the standard of care, enzalutamide, a structural analogue of apalutamide. Resistance develops in almost all CRPC patients within three months of beginning treatment. Herein, we report that both apalutamide and the structurally distinct darolutamide induce AKR1C3 expression in in vitro models of prostate cancer and are susceptible to AKR1C3-mediated resistance. This effect is countered by pretreatment with a potent and highly selective AKR1C3 inhibitor, sensitizing high AKR1C3 expressing prostate cancer cell lines to the action of both chemotherapeutics with a concomitant reduction in expression of AKR1C3 and the biomarker prostate-specific antigen.

MATERIALS
제품 번호
브랜드
제품 설명

Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-15, ascites fluid
Sigma-Aldrich
Anti-AKR1C3 antibody, Mouse monoclonal, clone NP6.G6.A6, purified from hybridoma cell culture
Sigma-Aldrich
Anti-Mouse IgG1 (γ1), CF350 antibody produced in goat, ~2 mg/mL, affinity isolated antibody, buffered aqueous solution