Cellular oxidative stress

Cellular oxidative stress activates an array of kinase pathways that modulate myocyte fate and
response to anthracyclines. Mitogen-activated protein kinases (MAPKs) and stress-activated
protein kinases (SAPKs) are important intracellular signal transduction intermediates, which
regulate cellular responses to stimuli by regulating gene expression, survival pathways,
proliferation, and growth. Anthracyclines activate the MAPK/ERK (extracellular signal-
regulated kinase) pathway via oxidant stress, and this appears to regulate cell survival. In
addition, anthracyclines may alter the ability of a myocyte to regulate prosurvival signaling. The
PI3K/Akt pathway is activated in the heart in response to many different growth factors,
including neuregulin, insulinlike growth factor-1 (IGF-1), and interleukins. In vitro studies show
that PI3K/Akt protects against anthracycline-induced apoptosis. There is some evidence that the
activity of these and other myocytoprotective pathways is reduced in the injured heart, thereby
increasing the susceptibility of myocytes to further anthracycline exposure. This may be one
mechanism to explain persistent ventricular remodeling late after anthracycline exposure, as well
as the increased susceptibility of the heart to cumulative anthracycline exposure.