Targeted Delivery of Doxorubicin to Mitochondria

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.

Mitochondrial Targeting of Doxorubicin Eliminates Nuclear Effects Associated with Cardiotoxicity

“…Our lab has previously demonstrated that mtDox ( Figure 1A) localizes to mitochondria of both HeLa and A2780 human cancer cell lines (20). In this study, the uptake and localization of untargeted Dox was compared to mtDox in a rat cardiomyocyte cell line (H9c2).…”

“…{Fulda, 2010 #29}(ref) While the therapeutic potential of harnessing the mitochondrial disruptive effects of Dox has been contemplated for over a decade (18), only recently have specific molecular targeting strategies been employed to deliver Dox to mitochondria. Such strategies include liposome encapsulation (19), chemical conjugation of mitochondrial targeting moieties (20,21) chemical modification (22), and nanoparticle encapsulation (23), all of which have demonstrated the capacity to induce cell death in cancer cells, validating this therapeutic strategy. Particularly promising is the ability of these targeted compounds to overcome clinically relevant resistance mechanisms that exist outside of mitochondria.…”

“…Particularly promising is the ability of these targeted compounds to overcome clinically relevant resistance mechanisms that exist outside of mitochondria. (20)(21)(22) Previous work has demonstrated that mitochondria-targeted Dox (mtDox, see Figure 1A for structure) is able to inhibit TopoII activity in vitro, leading to the induction of apoptotic cell death in cancer cells, while evading resistance mechanisms such as the upregulation of Pgp efflux pumps in the cellular membrane. (20) This phenomenon has been observed for a number of targeted anticancer agents and is likely the result of direct mitochondrial sequestration.…”

“…(20)(21)(22) Previous work has demonstrated that mitochondria-targeted Dox (mtDox, see Figure 1A for structure) is able to inhibit TopoII activity in vitro, leading to the induction of apoptotic cell death in cancer cells, while evading resistance mechanisms such as the upregulation of Pgp efflux pumps in the cellular membrane. (20) This phenomenon has been observed for a number of targeted anticancer agents and is likely the result of direct mitochondrial sequestration. (24) We propose that by leveraging this targeting approach, we can probe and eliminate the aforementioned nuclear effects associated with Dox-induced cardiotoxicity.…”

Validation of a Strategy for Cancer Therapy: Delivering Aminoglycoside Drugs to Mitochondria in HeLa Cells

“…On the other hand, mitochondria in human cancer cells are closely related to cancer cell proliferation, invasion, metastasis and even drug resistance mechanisms, because of the power exerted by cancer cells for the production of usable energy [6][7][8] . Thus, we hypothesized that the cellular uptake of AGs could kill cancer cells via mitochondrial toxicity, which would lead to an effective strategy for treating cancer in a different way from conventional anticancer agents.…”