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.
Highlights
The nitrogen mustard chlorambucil (Cbl) was one of the first anti-cancer drugs to be developed and used clinically [1,2]
Establishing the intramitochondrial target of mitochondria-targeted chlorambucil (mt-Cbl) In a previous study [11], we demonstrated that mt-Cbl was able to crosslink mtDNA and induce DNA lesions in vitro and we hypothesized that this form of damage resulted in the activation of cell death
These results indicate that it is alkylation of mtDNA by mt-Cbl that plays a crucial role in inducing cell death
Summary
The nitrogen mustard chlorambucil (Cbl) was one of the first anti-cancer drugs to be developed and used clinically [1,2]. This DNA alkylating agent was engineered from an original set of compounds, which included drugs such as chlormethine, to have a more favorable kinetic profile and decreased toxicity [3,4]. Chlorambucil functions as a mono- or di-alkylating agent by reacting primarily with the N7 of guanine to produce intra- or inter-strand crosslinks [5]. Formation of these crosslinks often stalls replication and transcription, leading to cell cycle arrest and apoptosis [6,7]. Patients often develop resistance to the drug necessitating the use of other agents, such as fludarabine [9,10]
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