Mechanism of doxorubicin cardiotoxicity evaluated by integrating multiple molecular effects into a biophysical model.

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 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 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 leak current (I ) until the consensus effects on APD and Ca 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 current and the sarcoplasmic reticulum I as the targets primarily responsible for the cardiotoxic effects on APD and Ca 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.