Attenuation of doxorubicin-induced cardiotoxicity in a human in vitro cardiac model by the induction of the NRF-2 pathway

Publication date: April 2019Source: Biomedicine & Pharmacotherapy, Volume 112Author(s): Lauren Tomlinson, Zhen Qi Lu, Robert A Bentley, Helen E. Colley, Craig Murdoch, Steven D. Webb, Michael J. Cross, Ian M. Copple, Parveen SharmaAbstractDose-dependent cardiotoxicity is the leading adverse reaction seen in cancer patients treated with doxorubicin. Currently, dexrazoxane is the only approved drug that can partially protect against this toxicity in patients, however, its administration is restricted to those patients receiving a high cumulative dose of anthracyclines. Investigations into the mechanisms of cardiotoxicity and efforts to improve cardioprotective strategies have been hindered by the limited availability of a phenotypically relevant in vitro adult human cardiac model system. Here, we adapted a readily reproducible, functional 3D human multi-cell type cardiac system to emulate patient responses seen with doxorubicin and dexrazoxane. We show that administration of two NRF2 gene inducers namely the semi-synthetic triterpenoid Bardoxolone methyl, and the isothiocyanate sulfurophane, result in cardioprotection against doxorubicin toxicity comparable to dexrazoxane as evidenced by an increase in cell viability and a decrease in the production of reactive oxygen species. We further show a synergistic attenuation of cardiotoxicity when the NRF2 inducers and dexrazoxane are used in tandem. Taken together, our data indicate that the 3D spheroid is a suitable model to investi...
Source: Biomedicine and Pharmacotherapy - Category: Drugs & Pharmacology Source Type: research