Metabolic carbonyl reduction of anthracyclines - role in cardiotoxicity and cancer resistance. Reducing enzymes as putative targets for novel cardioprotective and chemosensitizing agents.
作者： Kamil Piska , Paulina Koczurkiewicz , Adam Bucki , Katarzyna Wójcik-Pszczoła , Marcin Kołaczkowski
DOI: 10.1007/S10637-017-0443-2
关键词:
摘要: Anthracycline antibiotics (ANT), such as doxorubicin or daunorubicin, are a class of anticancer drugs that widely used in oncology. Although highly effective cancer therapy, their usefulness is greatly limited by cardiotoxicity. Possible mechanisms ANT cardiotoxicity include conversion to secondary alcohol metabolites (i.e. doxorubicinol, daunorubicinol) catalyzed carbonyl reductases (CBR) and aldo-keto (AKR). These suspected be more cardiotoxic than parent compounds. Moreover, overexpression ANT-reducing enzymes (CBR AKR) found many ANT-resistant cancers. The show decreased cytotoxic properties susceptible ABC-mediated efflux compounds; thus, metabolite formation considered one the resistance. Inhibitors CBR AKR were reduce resistance cells, therefore being investigated prospective cardioprotective chemosensitizing drug candidates. In this review, significance two-electron reduction ANT, including epirubicin, idarubicin, valrubicin, amrubicin, aclarubicin, especially doxorubicin, described with respect toxicity efficacy therapy. Additionally, inhibitors, monoHER, curcumin, (−)-epigallocatechin gallate, resveratrol, berberine pixantrone, modulating effect on activity characterized discussed potential mechanism action for novel therapeutics treatment.
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