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

ABSTRACT:

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 Ca²⁺ 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 equiv

SUBMITTER: Fernandez-Chas M 

PROVIDER: S-EPMC5811623 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature