Anthracyclines are included in clinical treatments against various
malignancies, but severe cardiotoxic side-effects and the development of resistance mechanisms limit their usefulness. Many aspects of the cellular response to
anthracyclines remain debated. The status of the main regulator of
iron homeostasis, namely the
RNA-binding activity of
iron regulatory proteins (IRPs), has been assessed herein for two types of human
tumor cells and their derived
doxorubicin-resistant sublines. IRPs were always fully activated in the latter, whereas only partial activation occurred in the former.
Doxorubicin exposure reversibly inactivated IRP1 in
small cell lung carcinoma (
GLC(4)) and
myelogenous leukemia (K562) cell lines, but was without effect in their derived
doxorubicin-resistant sublines. In contrast, adding
doxorubicin to cytosolic fractions of untreated cells or to purified IRPs led to the irreversible alteration of the
RNA-binding activity of IRP1. In these different conditions, interaction between
doxorubicin and the
iron regulatory system disturbs
iron metabolism, and cells having developed a resistance mechanism are tuned to maximize the
iron supply. The results reported herein may lead the path toward a better therapeutic management of
cancer patients receiving
doxorubicin by discriminating between the antiproliferative and cardiotoxic properties of this
anthracycline.