title: Ascorbate and endocytosed Motexafin gadolinium induce lysosomal rupture.
abstract: Motexafin gadolinium (MGd) sensitizes malignant cells to ionizing radiation, although the underlying mechanisms for uptake and sensitization are both unclear. Here we show that MGd is endocytosed by the clathrin-dependent pathway with ensuing lysosomal membrane permeabilization, most likely via formation of reactive oxygen species involving redox-active metabolites, such as ascorbate. We propose that subsequent apoptosis is a synergistic effect of irradiation and high MGd concentrations in malignant cells due to their pronounced endocytic activity. The results provide novel insights into the mode of action of this promising anti-cancer drug, which is currently under clinical trials.
authors.affiliation: Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Carsten
authors.initials: C
authors.lastname: Berndt
authors.forename: Tino
authors.initials: T
authors.lastname: Kurz
authors.forename: Sarah
authors.initials: S
authors.lastname: Bannenberg
authors.forename: Ralf
authors.initials: R
authors.lastname: Jacob
authors.forename: Arne
authors.initials: A
authors.lastname: Holmgren
authors.forename: Ulf T
authors.initials: UT
authors.lastname: Brunk
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000494:pharmacology*; D002460:Cell Line; D004705:Endocytosis / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D008247:Lysosomes / Q000187:drug effects*; D008665:Metalloporphyrins / Q000494:pharmacology*; D008856:Microscopy, Fluorescence; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D008665:Metalloporphyrins; D017382:Reactive Oxygen Species; C437683:motexafin gadolinium; D001205:Ascorbic Acid