Re-directing an alkylating agent to mitochondria alters drug target and cell death mechanism.

TitleRe-directing an alkylating agent to mitochondria alters drug target and cell death mechanism.
Publication TypeJournal Article
Year of Publication2013
AuthorsMourtada, R, Fonseca, SB, Wisnovsky, SP, Pereira, MP, Wang, X, Hurren, R, Parfitt, J, Larsen, L, Smith, RAJ, Murphy, MP, Schimmer, AD, Kelley, SO
JournalPLoS One
Volume8
Issue4
Paginatione60253
Date Published2013
ISSN1932-6203
KeywordsAnimals, Antineoplastic Agents, Alkylating, Apoptosis, Cell-Penetrating Peptides, Chlorambucil, Cross-Linking Reagents, DNA, Mitochondrial, Drug Delivery Systems, HeLa Cells, Humans, Leukemia, Mice, Mice, Inbred NOD, Mice, SCID, Mitochondria, Necrosis, Reactive Oxygen Species, Xenograft Model Antitumor Assays
Abstract

We have successfully delivered a reactive alkylating agent, chlorambucil (Cbl), to the mitochondria of mammalian cells. Here, we characterize the mechanism of cell death for mitochondria-targeted chlorambucil (mt-Cbl) in vitro and assess its efficacy in a xenograft mouse model of leukemia. Using a ρ° cell model, we show that mt-Cbl toxicity is not dependent on mitochondrial DNA damage. We also illustrate that re-targeting Cbl to mitochondria results in a shift in the cell death mechanism from apoptosis to necrosis, and that this behavior is a general feature of mitochondria-targeted Cbl. Despite the change in cell death mechanisms, we show that mt-Cbl is still effective in vivo and has an improved pharmacokinetic profile compared to the parent drug. These findings illustrate that mitochondrial rerouting changes the site of action of Cbl and also alters the cell death mechanism drastically without compromising in vivo efficacy. Thus, mitochondrial delivery allows the exploitation of Cbl as a promiscuous mitochondrial protein inhibitor with promising therapeutic potential.

DOI10.1371/journal.pone.0060253
Alternate JournalPLoS ONE
Citation Key10.1371/journal.pone.0060253
PubMed ID23585833
PubMed Central IDPMC3621862
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom
R01 CA157456 / CA / NCI NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada