title: Enhanced efficacy of bleomycin in bladder cancer cells by photochemical internalization.
abstract: Bleomycin is a cytotoxic chemotherapeutic agent widely used in cancer treatment. However, its efficacy in different cancers is low, possibly due to limited cellular internalization. In this study, a novel approach known as photochemical internalization (PCI) was explored to enhance bleomycin delivery in bladder cancer cells (human T24 and rat AY-27), as bladder cancer is a potential indication for use of PCI with bleomycin. The PCI technique was mediated by the amphiphilic photosensitizer disulfonated tetraphenyl chlorin (TPCS(2a)) and blue light (435 nm). Two additional strategies were explored to further enhance the cytotoxicity of bleomycin; a novel peptide drug ATX-101 which is known to impair DNA damage responses, and the protease inhibitor E-64 which may reduce bleomycin degradation by inhibition of bleomycin hydrolase. Our results demonstrate that the PCI technique enhances the bleomycin effect under appropriate conditions, and importantly we show that PCI-bleomycin treatment leads to increased levels of DNA damage supporting that the observed effect is due to increased bleomycin uptake. Impairing the DNA damage responses by ATX-101 further enhances the efficacy of the PCI-bleomycin treatment, while inhibiting the bleomycin hydrolase does not.
authors.affiliation: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, P.O. Box 8905, 7491 Trondheim, Norway.
authors.forename: Yan
authors.identifier: 0000-0003-4204-4928
authors.initials: Y
authors.lastname: Baglo
authors.affiliation: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, P.O. Box 8905, 7491 Trondheim, Norway.
authors.forename: Lars
authors.identifier: 0000-0002-7291-611X
authors.initials: L
authors.lastname: Hagen
authors.affiliation: PCI Biotech AS, Strandveien 55, 1366 Lysaker, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Høgset
authors.affiliation: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, P.O. Box 8905, 7491 Trondheim, Norway.
authors.forename: Finn
authors.identifier: 0000-0001-5794-828X
authors.initials: F
authors.lastname: Drabløs
authors.affiliation: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, P.O. Box 8905, 7491 Trondheim, Norway ; APIM Therapeutics AS, Sem Sælandsvei 14, 7084 Trondheim, Norway.
authors.forename: Marit
authors.initials: M
authors.lastname: Otterlei
authors.affiliation: Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, P.O. Box 8905, 7491 Trondheim, Norway.
authors.forename: Odrun A
authors.initials: OA
authors.lastname: Gederaas
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001761:Bleomycin / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage; D004249:DNA Damage / Q000187:drug effects; D006801:Humans; D055668:Photochemical Processes; D017319:Photosensitizing Agents / Q000008:administration & dosage*; D011166:Porphyrins / Q000008:administration & dosage; D051381:Rats; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: C520537:1,5-bis((2-(methylamino)ethyl)amino)-4,8-dihydroxyanthracene-9,10-dione; C587865:ATX-101 peptide; D000880:Anthraquinones; D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D017319:Photosensitizing Agents; D011166:Porphyrins; C559366:meso-tetraphenyl chlorin disulphonate; D001761:Bleomycin
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