title: Highly Selective Anti-Cancer Activity of Cholesterol-Interacting Agents Methyl-β-Cyclodextrin and Ostreolysin A/Pleurotolysin B Protein Complex on Urothelial Cancer Cells.
abstract: Cholesterol content can vary distinctly between normal and cancer cells, with elevated levels in cancer cells. Here, we investigated cholesterol sequestration with methyl-β-cyclodextrin (MCD), and pore-formation with the ostreolysin A/pleurotolysin B (OlyA/PlyB) protein complex that binds to cholesterol/sphingomyelin-rich membrane domains. We evaluated the effects on viability of T24 invasive and RT4 noninvasive human urothelial cancer cells and normal porcine urothelial (NPU) cells. Cholesterol content strongly correlated with cancerous transformation, as highest in the T24 high-grade invasive urothelial cancer cells, and lowest in NPU cells. MCD treatment induced prominent cell death of T24 cells, whereas OlyA/PlyB treatment resulted in greatly decreased viability of the RT4 low-grade noninvasive carcinoma cells. Biochemical and transmission electron microscopy analyses revealed that MCD and OlyA/PlyB induce necrotic cell death in these cancer cells, while viability of NPU cells was not significantly affected by either treatment. We conclude that MCD is more toxic for T24 high-grade invasive urothelial cancer cells, and OlyA/PlyB for RT4 low-grade noninvasive urothelial cancer cells, and neither is toxic for NPU cells. The cholesterol and cholesterol/sphingomyelin-rich membrane domains in urothelial cancer cells thus constitute a selective therapeutic target for elimination of urothelial cancer cells.
authors.affiliation: Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, Ljubljana, Slovenia.
authors.forename: Nataša
authors.initials: N
authors.lastname: Resnik
authors.affiliation: Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Jamova 39, Ljubljana, Slovenia.
authors.forename: Urška
authors.initials: U
authors.lastname: Repnik
authors.affiliation: Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, Ljubljana, Slovenia.
authors.forename: Mateja Erdani
authors.initials: ME
authors.lastname: Kreft
authors.affiliation: Department of Biology, Biotechnical Faculty, University of Ljubljana, Večna pot 111, Ljubljana, Slovenia.
authors.forename: Kristina
authors.initials: K
authors.lastname: Sepčić
authors.affiliation: Department of Biology, Biotechnical Faculty, University of Ljubljana, Večna pot 111, Ljubljana, Slovenia.
authors.forename: Peter
authors.initials: P
authors.lastname: Maček
authors.affiliation: Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Jamova 39, Ljubljana, Slovenia.
authors.forename: Boris
authors.initials: B
authors.lastname: Turk
authors.affiliation: Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, Ljubljana, Slovenia.
authors.forename: Peter
authors.initials: P
authors.lastname: Veranič
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D005656:Fungal Proteins / Q000494:pharmacology; D006460:Hemolysin Proteins / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D013552:Swine; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019459:Urothelium / Q000166:cytology / Q000187:drug effects; D047392:beta-Cyclodextrins / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D005656:Fungal Proteins; D006460:Hemolysin Proteins; D047392:beta-Cyclodextrins; C108732:methyl-beta-cyclodextrin; C461280:ostreolysin; C586632:pleurotolysin B, oyster mushroom; D002784:Cholesterol