title: Rerouting chlorambucil to mitochondria combats drug deactivation and resistance in cancer cells.
abstract: The difficulty of accessing the mitochondrial matrix has limited the targeting of therapeutics to this organelle. Here, we report, to our knowledge, the first successful delivery of an active DNA alkylating agent--chlorambucil--to mitochondria, and describe unexpected features that result from rerouting this drug within the cell. Mitochondrial targeting of this agent dramatically potentiates its activity, and promotes apoptotic cell death in a variety of cancer cell lines and patient samples. This retention of activity is observed even in cells with resistance to chlorambucil or disabled apoptotic triggering.
authors.affiliation: Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, ON M5S1A8, Canada.
authors.forename: Sonali B
authors.initials: SB
authors.lastname: Fonseca
authors.forename: Mark P
authors.initials: MP
authors.lastname: Pereira
authors.forename: Rida
authors.initials: R
authors.lastname: Mourtada
authors.forename: Marcela
authors.initials: M
authors.lastname: Gronda
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Horton
authors.forename: Rose
authors.initials: R
authors.lastname: Hurren
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Schimmer
authors.forename: Shana O
authors.initials: SO
authors.lastname: Kelley
mesh_terms: D000478:Alkylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology*; D001692:Biological Transport; D045744:Cell Line, Tumor; D002699:Chlorambucil / Q000378:metabolism* / Q000494:pharmacology*; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D002699:Chlorambucil