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Published on: May 12, 2020
Structural modifications of mitochondria-targeted chlorambucil alter cell death mechanism but preserve MDR evasion
Sae Rin Jean1, Mark P Pereira, Shana O Kelley
1Department of Chemistry, Faculty of Arts and Science, ‡Department of Biochemistry, Faculty of Medicine, and §Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto , Toronto, Ontario Canada.
Abstract:
Multidrug resistance (MDR) remains one of the major obstacles in chemotherapy, potentially rendering a multitude of drugs ineffective. Previously, we have demonstrated that mitochondrial targeting of DNA damaging agents is a promising tool for evading a number of common resistance factors that are present in the nucleus or cytosol. In particular, mitochondria-targeted chlorambucil (mt-Cbl) has increased potency and activity against resistant cancer cells compared to the parent compound chlorambucil (Cbl). However, it was found that, due to its high reactivity, mt-Cbl induces a necrotic type of cell death via rapid nonspecific alkylation of mitochondrial proteins. Here, we demonstrate that by tuning the alkylating activity of mt-Cbl via chemical modification, the rate of generation of protein adducts can be reduced, resulting in a shift of the cell death mechanism from necrosis to a more controlled apoptotic pathway. Moreover, we demonstrate that all of the modified mt-Cbl compounds effectively evade MDR resulting from cytosolic GST-μ upregulation by rapidly accumulating in mitochondria, inducing cell death directly from within. In this study, we systematically elucidated the advantages and limitations of targeting alkylating agents with varying reactivity to mitochondria.
Insights
Modifying mitochondria-targeted chlorambucil (mt-Cbl) shifts cancer cell death from necrosis to apoptosis. These modified mt-Cbl compounds effectively overcome multidrug resistance (MDR) by targeting cancer cells directly within mitochondria.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Multidrug resistance (MDR) is a significant challenge in chemotherapy, reducing drug efficacy.
- Mitochondrial targeting of DNA damaging agents offers a strategy to bypass common resistance mechanisms.
- Mitochondria-targeted chlorambucil (mt-Cbl) shows enhanced potency against resistant cells but induces necrosis due to high reactivity.
Purpose of the Study:
- To investigate the effect of modifying mt-Cbl's alkylating activity on cell death pathways.
- To assess the efficacy of modified mt-Cbl compounds in overcoming MDR.
- To elucidate the advantages and limitations of targeting mitochondria with alkylating agents of varying reactivity.
Main Methods:
- Chemical modification of mt-Cbl to tune its alkylating activity.
- Assessment of cell death mechanisms (necrosis vs. apoptosis).
- Evaluation of MDR evasion in cancer cells with upregulated cytosolic GST-μ.
Main Results:
- Reduced alkylating activity of modified mt-Cbl compounds shifts cell death from necrosis to apoptosis.
- Modified mt-Cbl compounds effectively evade MDR caused by GST-μ upregulation.
- Rapid accumulation of mt-Cbl derivatives within mitochondria ensures direct intracellular action.
Conclusions:
- Tuning the reactivity of mitochondria-targeted alkylating agents can control the mode of cancer cell death.
- Mitochondrial targeting provides a viable strategy to overcome specific MDR mechanisms.
- This study systematically analyzes the potential and constraints of mitochondria-targeted alkylating chemotherapy.
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