Key result
Inhibitors of carbonyl reductases and aldo-keto reductases may reduce anthracycline-induced cardiotoxicity and cancer resistance by preventing the formation of toxic secondary alcohol metabolites.
Why the study?
Do carbonyl reductase and aldo-keto reductase inhibitors reduce anthracycline-induced cardiotoxicity and cancer resistance?
Do carbonyl reductase and aldo-keto reductase inhibitors reduce anthracycline-induced cardiotoxicity and cancer resistance?
Carbonyl reductase and aldo-keto reductase inhibitors represent a potential strategy to mitigate anthracycline-induced cardiotoxicity and overcome cancer cell resistance.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for reductase inhibition to mitigate anthracycline cardiotoxicity; prospective trials needed before clinical adoption.
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.
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Piska et al. (2017) conducted a review in Anthracycline-induced cardiotoxicity and cancer resistance. Carbonyl reductase (CBR) and aldo-keto reductase (AKR) inhibitors was evaluated. Inhibitors of carbonyl reductases and aldo-keto reductases may reduce anthracycline-induced cardiotoxicity and cancer resistance by preventing the formation of toxic secondary alcohol metabolites.
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