Targeted Delivery of Doxorubicin to Mitochondria
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Abstract
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