Hintzpeter, J., Seliger, J. M., Hofman, J., Martin, H. J., Wsol, V. and Maser, Edmund (2016) Inhibition of human anthracycline reductases by emodin - A possible remedy for anthracycline resistance. Toxicology and Applied Pharmacology, 293 . pp. 21-29. DOI 10.1016/j.taap.2016.01.003.

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Abstract

The clinical application of anthracyclines, like daunorubicin and doxorubicin, is limited by two factors: dose related cardiotoxicity and drug resistance. Both have been linked to reductive metabolism of the parent drug to their metabolites daunorubicinol and doxorubicinol, respectively. These metabolites show significantly less anti-neoplastic properties as their parent drugs and accumulate in cardiac tissue leading to chronic cardiotoxicity. Therefore, we aimed to identify novel and potent natural inhibitors for anthracycline reductases, which enhance the anticancer effect of anthracyclines by preventing the development of anthracycline resistance. Human enzymes responsible for the reductive metabolism of daunorubicin were tested for their sensitivity towards anthrachinones, in particular emodin and anthraflavic acid. Intense inhibition kinetic data for the most effective daunorubicin reductases, including IC50-and K-i-values, the mode of inhibition, as well as molecular docking, were compiled. Subsequently, a cytotoxicity profile and the ability of emodin to reverse daunorubicin resistance were determined using multiresistant A549 lung cancer and HepG2 liver cancer cells. Emodin potently inhibited the four main human daunorubicin reductases in vitro. Further, we could demonstrate that emodin is able to synergistically sensitize human cancer cells towards daunorubicin at clinically relevant concentrations. Therefore, emodin may yield the potential to enhance the therapeutic effectiveness of anthracyclines by preventing anthracycline resistance via inhibition of the anthracycline reductases. In symphony with its known pharmacological properties, emodin might be a compound of particular interest in the management of anthracycline chemotherapy efficacy and their adverse effects. (C) 2016 Elsevier Inc All rights reserved.

Document Type:	Article
Additional Information:	Times Cited: 0 Hintzpeter, Jan Seliger, Jan Moritz Hofman, Jakub Martin, Hans-Joerg Wsol, Vladimir Maser, Edmund
Keywords:	AKR, aldo-keto reductase, SDR, short-chain dehydrogenase/reductase, DAUN, daunorubicin, DOX, doxorubicin, DAUNOL, daunorubicinol, DOXOL, doxorubicinol
Research affiliation:	Kiel University OceanRep > The Future Ocean - Cluster of Excellence
Refereed:	Yes
Open Access Journal?:	No
Publisher:	Elsevier
Projects:	Future Ocean
Date Deposited:	07 Mar 2017 10:46
Last Modified:	23 Sep 2019 22:09
URI:	https://oceanrep.geomar.de/id/eprint/36135

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