title: A selective mitochondrial-targeted chlorambucil with remarkable cytotoxicity in breast and pancreatic cancers.
abstract: Nitrogen mustards, widely used as chemotherapeutics, have limited safety and efficacy. Mitochondria lack a functional nucleotide excision repair mechanism to repair DNA adducts and are sensitive to alkylating agents. Importantly, cancer cells have higher intrinsic mitochondrial membrane potential (Δψmt) than normal cells. Therefore, selectively targeting nitrogen mustards to cancer cell mitochondria based on Δψmt could overcome those limitations. Herein, we describe the design, synthesis, and evaluation of Mito-Chlor, a triphenylphosphonium derivative of the nitrogen mustard chlorambucil. We show that Mito-Chlor localizes to cancer cell mitochondria where it acts on mtDNA to arrest cell cycle and induce cell death, resulting in a 80-fold enhancement of cell kill in a panel of breast and pancreatic cancer cell lines that are insensitive to the parent drug. Significantly, Mito-Chlor delayed tumor progression in a mouse xenograft model of human pancreatic cancer. This is a first example of repurposing chlorambucil, a drug not used in breast and pancreatic cancer treatment, as a novel drug candidate for these diseases.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California , 1985 Zonal Avenue, Los Angeles, California 90089, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Millard
authors.forename: John D
authors.initials: JD
authors.lastname: Gallagher
authors.forename: Bogdan Z
authors.initials: BZ
authors.lastname: Olenyuk
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D001943:Breast Neoplasms / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002699:Chlorambucil / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D006657:Histones; D017382:Reactive Oxygen Species; D002699:Chlorambucil