Re-Directing an Alkylating Agent to Mitochondria Alters Drug Target and Cell Death Mechanism

Rida Mourtada, Sonali B. Fonseca, Simon P. Wisnovsky, Mark P. Pereira, Xiaoming Wang, Rose Hurren, Jeremy Parfitt, Lesley Larsen, Robin A.J. Smith, Michael P. Murphy, Aaron D. Schimmer, Shana O. Kelley

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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.

Original languageEnglish (US)
Article numbere60253
JournalPloS one
Volume8
Issue number4
DOIs
StatePublished - Apr 9 2013
Externally publishedYes

ASJC Scopus subject areas

  • General

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