Isocitrate dehydrogenase 2 inhibitor enasidenib synergizes daunorubicin cytotoxicity by targeting aldo-keto reductase 1C3.

Abstract

Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Andro Haddad Supervisor: prof. Ing. Vladimír Wsól, Ph.D. Consultant: Anselm Morell García, Ph.D. Title of diploma thesis: ISOCITRATE DEHYDROGENASE 2 INHIBITOR ENASIDENIB SYNERGIZES DAUNORUBICIN CYTOTOXICITY BY TARGETING ALDO-KETO REDUCTASE 1C3 Treatment with anthracyclines is crucial in treating several oncologic disorders. However, several molecular mechanisms hinder the effectivity of anthracyclines, which is a significant obstacle in cancer therapy. Carbonyl reducing enzymes (CREs), a type of NAD(P)H-dependent oxidoreductase, contribute to anthracycline resistance by reducing these drugs to fewer active alcohols. These enzymes also play a role in the proliferation and differentiation of cancer cells, leading to increased tumour aggressiveness. Therefore, targeting these enzymes is essential for effective anticancer therapy. This study aimed to uncover the potential off-targets of the isocitrate dehydrogenase (IDH) inhibitor enasidenib (ENA) that could counteract the resistance to anthracycline, specifically in relation to the detoxification role of CREs. For this, we screened the ability of ENA to inhibit different recombinant CREs that can reduce daunorubicin (Daun) to daunorubicinol...