title: A new ER-specific photosensitizer unravels (1)O2-driven protein oxidation and inhibition of deubiquitinases as a generic mechanism for cancer PDT.
abstract: Photosensitizers (PS) are ideally devoid of any activity in the absence of photoactivation, and rely on molecular oxygen for the formation of singlet oxygen ((1)O2) to produce cellular damage. Off-targets and tumor hypoxia therefore represent obstacles for the use of PS for cancer photodynamic therapy. Herein, we describe the characterization of OR141, a benzophenazine compound identified through a phenotypic screening for its capacity to be strictly activated by light and to kill a large variety of tumor cells under both normoxia and hypoxia. This new class of PS unraveled an unsuspected common mechanism of action for PS that involves the combined inhibition of the mammalian target of rapamycin (mTOR) signaling pathway and proteasomal deubiquitinases (DUBs) USP14 and UCH37. Oxidation of mTOR and other endoplasmic reticulum (ER)-associated proteins drives the early formation of high molecular weight (MW) complexes of multimeric proteins, the concomitant blockade of DUBs preventing their degradation and precipitating cell death. Furthermore, we validated the antitumor effects of OR141 in vivo and documented its highly selective accumulation in the ER, further increasing the ER stress resulting from (1)O2 generation upon light activation.
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Pinto
authors.affiliation: Institute of Condensed Matter and Nanosciences Molecules, Solids and Reactivity (IMCN/MOST), Université catholique de Louvain, Louvain-la-Neuve, Belgium.
authors.forename: Y
authors.initials: Y
authors.lastname: Mace
authors.affiliation: Institute of Condensed Matter and Nanosciences Molecules, Solids and Reactivity (IMCN/MOST), Université catholique de Louvain, Louvain-la-Neuve, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Drouet
authors.affiliation: Pharmacognosy Research Group (GNOS), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain, Louvain-la-Neuve, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Bony
authors.affiliation: Institute of Condensed Matter and Nanosciences Molecules, Solids and Reactivity (IMCN/MOST), Université catholique de Louvain, Louvain-la-Neuve, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Boidot
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium.
authors.forename: N
authors.initials: N
authors.lastname: Draoui
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium.
authors.forename: I
authors.initials: I
authors.lastname: Lobysheva
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Corbet
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Polet
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Martherus
authors.affiliation: Institute of Condensed Matter and Nanosciences Molecules, Solids and Reactivity (IMCN/MOST), Université catholique de Louvain, Louvain-la-Neuve, Belgium.
authors.forename: Q
authors.initials: Q
authors.lastname: Deraedt
authors.affiliation: Systems Biology Ireland, Conway Institute, Belfield, Dublin 4, Ireland.
authors.forename: J
authors.initials: J
authors.lastname: Rodríguez
authors.affiliation: Institute of Condensed Matter and Nanosciences Molecules, Solids and Reactivity (IMCN/MOST), Université catholique de Louvain, Louvain-la-Neuve, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Lamy
authors.affiliation: Institute of Condensed Matter and Nanosciences Molecules, Solids and Reactivity (IMCN/MOST), Université catholique de Louvain, Louvain-la-Neuve, Belgium.
authors.forename: O
authors.initials: O
authors.lastname: Schicke
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Delvaux
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Louis
authors.affiliation: Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Kiss
authors.affiliation: Systems Biology Ireland, Conway Institute, Belfield, Dublin 4, Ireland.
authors.forename: A V
authors.initials: AV
authors.lastname: Kriegsheim
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium.
authors.forename: C
authors.initials: C
authors.lastname: Dessy
authors.affiliation: Institute of Condensed Matter and Nanosciences Molecules, Solids and Reactivity (IMCN/MOST), Université catholique de Louvain, Louvain-la-Neuve, Belgium.
authors.forename: B
authors.initials: B
authors.lastname: Elias
authors.affiliation: Pharmacognosy Research Group (GNOS), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain, Louvain-la-Neuve, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Quetin-Leclercq
authors.affiliation: Institute of Condensed Matter and Nanosciences Molecules, Solids and Reactivity (IMCN/MOST), Université catholique de Louvain, Louvain-la-Neuve, Belgium.
authors.forename: O
authors.initials: O
authors.lastname: Riant
authors.affiliation: Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium.
authors.forename: O
authors.initials: O
authors.lastname: Feron
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D000072017:Deubiquitinating Enzymes / Q000037:antagonists & inhibitors*; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010084:Oxidation-Reduction; D010100:Oxygen / Q000494:pharmacology*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
chemical_list: D017319:Photosensitizing Agents; D058570:TOR Serine-Threonine Kinases; D000072017:Deubiquitinating Enzymes; D046988:Proteasome Endopeptidase Complex; D010100:Oxygen