title: Organometallic Rhenium Complexes Divert Doxorubicin to the Mitochondria.
abstract: Doxorubicin, a well-established chemotherapeutic agent, is known to accumulate in the cell nucleus. By using ICP-MS, we show that the conjugation of two small organometallic rhenium complexes to this structural motif results in a significant redirection of the conjugates from the nucleus to the mitochondria. Despite this relocation, the two bioconjugates display excellent toxicity toward HeLa cells. In addition, we carried out a preliminarily investigation of aspects of cytotoxicity and present evidence that the conjugates disrupt the mitochondrial membrane potential, are strong inhibitors of human Topoisomerase II, and induce apoptosis. Such derivatives may enhance the therapeutic index of the aggressive parent drug and overcome drug resistance by influencing nuclear and mitochondrial homeostasis.
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Imstepf
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pierroz
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Rubbiani
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Felber
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fox
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
authors.forename: Gilles
authors.initials: G
authors.lastname: Gasser
authors.affiliation: Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland. ariel@chem.uzh.ch.
authors.forename: Roger
authors.initials: R
authors.lastname: Alberto
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics*; D004317:Doxorubicin / Q000493:pharmacokinetics*; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects*; D009942:Organometallic Compounds / Q000494:pharmacology*; D012211:Rhenium / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D009942:Organometallic Compounds; D012211:Rhenium; D004317:Doxorubicin
keywords: antitumor compounds; doxorubicin; drug targeting; mitochondria; organometallic drugs