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Mechanism of doxorubicin cardiotoxicity evaluated by integrating multiple molecular effects into a biophysical model
Author(s) -
FernandezChas M,
Curtis M J,
Niederer S A
Publication year - 2018
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14104
Subject(s) - cardiotoxicity , doxorubicin , pharmacology , endoplasmic reticulum , in silico , chemistry , medicine , toxicity , biochemistry , chemotherapy , gene
Background and Purpose Doxorubicin (DOX) is an effective cancer therapeutic agent but causes therapy‐limiting cardiotoxicity. The effects of DOX and its metabolite doxorubicinol (DOXL) on individual channels have been well characterized in isolation. However, it is unknown how the action and interaction of affected channels combine to generate the phenotypic cardiotoxic outcome. We sought to develop an in silico model that links drug effects on channels to action potential duration (APD) and intracellular Ca 2+ concentration in order to address this gap in knowledge. Experimental Approach We first propose two methods to obtain, from published values, consensus drug effects on the currents of individual channels, transporters and pumps. Separately, we obtained equivalent values for APD and Ca 2+ concentration (the readouts used as surrogates for cardiotoxicity). Once derived, the consensus effects on the currents were incorporated into established biophysical models of the cardiac myocyte and were refined adjusting the sarcoplasmic reticulum Ca 2+ leak current ( I Leak ) until the consensus effects on APD and Ca 2+ dynamics were replicated. Using factorial analysis, we then quantified the relative contribution of each channel to DOX and DOXL cardiotoxicity. Key Results The factorial analysis identified the rapid delayed rectifying K + current, the L‐type Ca 2+ current and the sarcoplasmic reticulum I Leak as the targets primarily responsible for the cardiotoxic effects on APD and Ca 2+ dynamics. Conclusions and Implications This study provides insight into the mechanisms of DOX‐induced cardiotoxicity and a framework for the development of future diagnostic and therapeutic strategies.