title: Imidazoacridinone-dependent lysosomal photodestruction: a pharmacological Trojan horse approach to eradicate multidrug-resistant cancers.
abstract: Multidrug resistance (MDR) remains a primary hindrance to curative cancer therapy. Thus, introduction of novel strategies to overcome MDR is of paramount therapeutic significance. Sequestration of chemotherapeutics in lysosomes is an established mechanism of drug resistance. Here, we show that MDR cells display a marked increase in lysosome number. We further demonstrate that imidazoacridinones (IAs), which are cytotoxic fluorochromes, undergo a dramatic compartmentalization in lysosomes because of their hydrophobic weak base nature. We hence developed a novel photoactivation-based pharmacological Trojan horse approach to target and eradicate MDR cancer cells based on photo-rupture of IA-loaded lysosomes and tumor cell lysis via formation of reactive oxygen species. Illumination of IA-loaded cells resulted in lysosomal photodestruction and restoration of parental cell drug sensitivity. Lysosomal photodestruction of MDR cells overexpressing the key MDR efflux transporters ABCG2, ABCB1 or ABCC1 resulted in 10- to 52-fold lower IC(50) values of various IAs, thereby restoring parental cell sensitivity. Finally, in vivo application of this photodynamic therapy strategy after i.v. injection of IAs in human ovarian tumor xenografts in the chorioallantoic membrane model revealed selective destruction of tumors and their associated vasculature. These findings identify lysosomal sequestration of IAs as an Achilles heel of MDR cells that can be harnessed to eradicate MDR tumor cells via lysosomal photodestruction.
authors.affiliation: Department of Biology, The Fred Wyszkowski Cancer Research Laboratory, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Adar
authors.forename: M
authors.initials: M
authors.lastname: Stark
authors.forename: E E
authors.initials: EE
authors.lastname: Bram
authors.forename: P
authors.initials: P
authors.lastname: Nowak-Sliwinska
authors.forename: H
authors.initials: H
authors.lastname: van den Bergh
authors.forename: G
authors.initials: G
authors.lastname: Szewczyk
authors.forename: T
authors.initials: T
authors.lastname: Sarna
authors.forename: A
authors.initials: A
authors.lastname: Skladanowski
authors.forename: A W
authors.initials: AW
authors.lastname: Griffioen
authors.forename: Y G
authors.initials: YG
authors.lastname: Assaraf
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D054831:Acridones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D002645:Chickens; D002738:Chloroquine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004625:Embryo, Nonmammalian; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007834:Lasers; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010782:Photolysis / Q000187:drug effects* / Q000528:radiation effects; D017319:Photosensitizing Agents / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D054831:Acridones; D002738:Chloroquine; D007093:Imidazoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D017319:Photosensitizing Agents; D017382:Reactive Oxygen Species; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C421109:multidrug resistance-associated protein 1