Inhibition of human anthracycline reductases by emodin - A possible remedy for anthracycline resistance.

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 Ki-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.

• Authors: Jan Hintzpeter, Jan Moritz Seliger, Jakub Hofman, Hans-Joerg Martin, Vladimir Wsol, Edmund Maser
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 293 Pg. 21-9 (Feb 15 2016) ISSN: 1096-0333 [Electronic] United States
• PMID: 26773812 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Anthraquinones
• Antibiotics, Antineoplastic
• Protein Kinase Inhibitors
• Oxidoreductases
• Emodin
• 2,6-dihydroxyanthraquinone
• Daunorubicin

Topics

• Anthraquinones (pharmacology)
• Antibiotics, Antineoplastic (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Daunorubicin (pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Emodin (pharmacology)
• Humans
• Molecular Docking Simulation
• Oxidoreductases (antagonists & inhibitors, metabolism)
• Protein Kinase Inhibitors (pharmacology)