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Please use this identifier to cite or link to this item: http://hdl.handle.net/1807/33466

Title: A Journey down the Cell Death Pathway of Mitochondria-targeted Chlorambucil
Authors: Mourtada, Rida
Advisor: Kelley, Shana O.
Department: Pharmaceutical Sciences
Keywords: Mitochondria
Mitochondria Penetrating Peptide
Cell Death
Issue Date: 26-Nov-2012
Abstract: Our lab recently demonstrated that retargeting an alkylating agent, chlorambucil (Cbl), to the mitochondrion is a viable strategy to restore drug activity and overcome drug resistance in cancer. The mechanism of action of the mitochondria-targeted chlorambucil (mt-Cbl) was studied using a cervical carcinoma model. It was discovered that mt-Cbl bound to mitochondrial DNA and various mitochondrial proteins. A ρ° model revealed that the toxicity of mt-Cbl is largely dependent on its protein targets. Damage induced by mt-Cbl was found to result in the activation of several modes of caspase-independent cell death including necrosis. In contrast, Cbl was found to only activate caspase-dependent cell death that is highly sensitive to caspase inhibition. These results illustrate that the ability of mt-Cbl to activate various orthogonal cell death pathways is what allows mt-Cbl to bypass several drug resistance mechanisms, thus making mitochondrial retargeting a lucrative strategy for future anticancer drug development.
URI: http://hdl.handle.net/1807/33466
Appears in Collections:Master

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