Inhibition of Anthracycline Alcohol Metabolite Formation in Human Heart Cytosol: A Potential Role for Several Promising Drugs

Abstract

The clinical efficacy of anthracyclines (e.g., doxorubicin and daunorubicin) in cancer therapy is limited by their severe cardiotoxicity, the etiology of which is still not fully understood. The development of anthracycline-induced cardiomyopathy has been found to correlate with myocardial formation and accumulation of anthracycline secondary alcohol metabolites (e.g., doxorubicinol and daunorubicinol) that are produced by distinct cytosolic NADPH-dependent reductases. The aim of the current study is to identify chemical compounds capable of inhibiting myocardial reductases implied in anthracycline reductive metabolism in an attempt to decrease the production of cardiotoxic C-13 alcohol metabolites. Among the variety of tested compounds (metal chelators, radical scavengers, antioxidants, b-blockers, nitrone spin traps, and lipid-lowering drugs), ebselen, cyclopentenone prostaglandins, nitric oxide donors, and short-chain coenzyme Q analogs resulted in being effective inhibitors of both doxorubicinol and daunorubicinol formation. In particular, ebselen (as well as ebselen diselenide, its storage form in the cells) was the most potent inhibitor of cardiotoxic anthracycline alcohol metabolites with 50% inhibition of doxorubicinol formation at 0.2 mol Eq of ebselen with respect to doxorubicin concentration. The high efficacy, together with its favorable pharmacological profile (low toxicity, lack of adverse effects, and metabolic stability) portends ebselen as a promising cardioprotective agent against anthracycline-induced cardiotoxicity.

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“…Mean C max of doxorubicinol levels were near the limits of detection (4.17–13.7 ng/mL). The latter finding may explain decreased or absent cardiotoxicity after ALDOX administration 67. The mean circulating half-life of ALDOX was measured at 20.1–21.1 h. V D was 3.96–4.08 L/m 2 .…”

“…A key methodological difference in this second PK study was inclusion of analyses specifically investigating free DOX and the metabolite doxorubicinol, as well as albumin-bound DOX. Doxorubicinol is proposed to play a major role in DOX cardiotoxicity 67. After the initial dose of DOX, the time to peak plasma concentrations (t max ) of ALDOX and free DOX were similar (0.75 and 0.58 h for 230 mg/m 2 [170 mg/m 2 DE] and 1.00 and 0.68 h for 350 mg/m 2 [260 mg/m 2 DE], respectively).…”

Development and Therapeutic Potential of Selenazo Compounds

“…70 Additionally, EBS has a special relevance as a promising cardioprotective agent against cardiotoxicity induced by doxorubicin (DOX) and daunorubicin, the two anthracyclines used in cancer therapy. 71 Endothelial dysfunction in uremia may be induced by accumulation of ROS, and deficient levels of glutathione peroxidase-3 (GPx3) may cause the development of kidney disease-induced cardiac risk. Thus, the potentiation of the antioxidant pathways by using GPx mimetic EBS can be an effective strategy to reduce the cardiovascular risk.…”

Metabolic carbonyl reduction of anthracyclines — role in cardiotoxicity and cancer resistance. Reducing enzymes as putative targets for novel cardioprotective and chemosensitizing agents

“…An organoselenium drug, ebselen, a cytoprotective, anti-inflammatory and antioxidant agent, has been found to be a non-competitive inhibitor of DOXol formation in the cytosol [61]. Hydroxy-PP-Me, a derivative of the Src kinase inhibitor PP2, through CBR1 inhibition, induced a 25% increase of DAUN cytotoxicity in A549 cells [62].…”