2 research outputs found
Targeted Delivery of Doxorubicin to Mitochondria
Several families of highly effective
anticancer drugs are selectively
toxic to cancer cells because they disrupt nucleic acid synthesis
in the nucleus. Much less is known, however, about whether interfering
with nucleic acid synthesis in the mitochondria would have significant
cellular effects. In this study, we explore this with a mitochondrially
targeted form of the anticancer drug doxorubicin, which inhibits DNA
topoisomerase II, an enzyme that is both in mitochondria and nuclei
of human cells. When doxorubicin is attached to a peptide that targets
mitochondria, it exhibits significant toxicity. However, when challenged
with a cell line that overexpresses a common efflux pump, it does
not exhibit the reduced activity of the nuclear-localized parent drug
and resists being removed from the cell. These results indicate that
targeting drugs to the mitochondria provides a means to limit drug
efflux and provide evidence that a mitochondrially targeted DNA topoisomerase
poison is active within the organelle
Mitochondrial Targeting of Doxorubicin Eliminates Nuclear Effects Associated with Cardiotoxicity
The highly effective anticancer agent
doxorubicin (Dox) is a frontline
drug used to treat a number of cancers. While Dox has a high level
of activity against cancer cells, its clinical use is often complicated
by dose-limiting cardiotoxicity. While this side effect has been linked
to the drug’s direct activity in the mitochondria of cardiac
cells, recent studies have shown that these result primarily from
downstream effects of nuclear DNA damage. Our lab has developed a
mitochondrially targeted derivative of Dox that enables the selective
study of toxicity generated by the presence of Dox in the mitochondria
of human cells. We demonstrate that mitochondria-targeted doxorubicin
(mtDox) lacks any direct nuclear effects in H9c2 rat cardiomyocytes,
and that these cells are able to undergo mitochondrial biogenesis.
This recovery response compensates for the mitotoxic effects of Dox
and prevents cell death in cardiomyocytes. Furthermore, cardiac toxicity
was only observed in Dox but not mtDox treated mice. This study supports
the hypothesis that mitochondrial damage is not the main source of
the cardiotoxic effects of Dox