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.

Keywords: Anthracyclines; Anticancer agents; Cardiotoxicity; Drug metabolism; Pharmacokinetics; Resistance.

Fig. 1

Two-electron reduction of DOX

Fig. 2

Decreased activity of DOXol may result from increased efflux, intracellular distribution outside the nucleus, and decreased affinity to DNA

Fig. 3

Flavone and chalcone structures

Fig. 4

Molecular structures of various CBR and/or AKR inhibitors

Fig. 5

Crystal structure of CBR1 protein (3BHJ) [64]. NADP⁺ cofactor bound in the active site of the enzyme. Substrate mimic inhibitor OH-PP bound in the glutathione (GSH) binding site near the catalytic triad amino acids: Ser139, Tyr193 and Lys197. Amino acid residues engaged in ligand binding (within 4 Å from the ligand atoms) are displayed as sticks, whereas crucial residues, i.e. forming hydrogen bonds (dotted yellow lines) and π-π stacking (dotted blue lines), are represented as thick sticks