title: Metabolic carbonyl reduction of anthracyclines - role in cardiotoxicity and cancer resistance. Reducing enzymes as putative targets for novel cardioprotective and chemosensitizing agents.
abstract: Anthracycline antibiotics (ANT), such as doxorubicin or daunorubicin, are a class of anticancer drugs that are widely used in oncology. Although highly effective in cancer therapy, their usefulness is greatly limited by their cardiotoxicity. Possible mechanisms of ANT cardiotoxicity include their conversion to secondary alcohol metabolites (i.e. doxorubicinol, daunorubicinol) catalyzed by carbonyl reductases (CBR) and aldo-keto reductases (AKR). These metabolites are suspected to be more cardiotoxic than their parent compounds. Moreover, overexpression of ANT-reducing enzymes (CBR and AKR) are found in many ANT-resistant cancers. The secondary metabolites show decreased cytotoxic properties and are more susceptible to ABC-mediated efflux than their parent compounds; thus, metabolite formation is considered one of the mechanisms of cancer resistance. Inhibitors of CBR and AKR were found to reduce the cardiotoxicity of ANT and the resistance of cancer cells, and therefore are being investigated as prospective cardioprotective and chemosensitizing drug candidates. In this review, the significance of a two-electron reduction of ANT, including daunorubicin, epirubicin, idarubicin, valrubicin, amrubicin, aclarubicin, and especially doxorubicin, is described with respect to toxicity and efficacy of therapy. Additionally, CBR and AKR inhibitors, including monoHER, curcumin, (-)-epigallocatechin gallate, resveratrol, berberine or pixantrone, and their modulating effect on the activity of ANT is characterized and discussed as potential mechanism of action for novel therapeutics in cancer treatment.
authors.affiliation: Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland. kamil.piska@uj.edu.pl.
authors.forename: Kamil
authors.initials: K
authors.lastname: Piska
authors.affiliation: Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Koczurkiewicz
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Bucki
authors.affiliation: Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Wójcik-Pszczoła
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kołaczkowski
authors.affiliation: Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Pękala
mesh_terms: D000074408:Aldo-Keto Reductases / Q000037:antagonists & inhibitors*; D000818:Animals; D018943:Anthracyclines / Q000009:adverse effects* / Q000493:pharmacokinetics; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000493:pharmacokinetics; D000074409:Carbonyl Reductase (NADPH) / Q000037:antagonists & inhibitors*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D066126:Cardiotoxicity / Q000209:etiology / Q000517:prevention & control*; D019008:Drug Resistance, Neoplasm; D006801:Humans
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D000074408:Aldo-Keto Reductases; D000074409:Carbonyl Reductase (NADPH)
keywords: Anthracyclines; Anticancer agents; Cardiotoxicity; Drug metabolism; Pharmacokinetics; Resistance