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.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/33466 |
| Date | 26 November 2012 |
| Creators | Mourtada, Rida |
| Contributors | Kelley, Shana O. |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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