title: Structural modifications of mitochondria-targeted chlorambucil alter cell death mechanism but preserve MDR evasion.
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.
authors.affiliation: Department 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.
authors.forename: Sae Rin
authors.initials: SR
authors.lastname: Jean
authors.forename: Mark P
authors.initials: MP
authors.lastname: Pereira
authors.forename: Shana O
authors.initials: SO
authors.lastname: Kelley
mesh_terms: D000477:Alkylating Agents / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D016923:Cell Death; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects; D002470:Cell Survival; D002699:Chlorambucil / Q000008:administration & dosage* / Q000737:chemistry; D003124:Colorimetry; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects; D004249:DNA Damage; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008928:Mitochondria / Q000378:metabolism*; D009336:Necrosis; D010051:Ovarian Neoplasms / Q000188:drug therapy*
chemical_list: D000477:Alkylating Agents; D000970:Antineoplastic Agents; D002699:Chlorambucil; D045304:Cytochromes c; D005982:Glutathione Transferase