title: Imaging Sites of Inhibition of Proteolysis in Pathomimetic Human Breast Cancer Cultures by Light-Activated Ruthenium Compound.
abstract: The cysteine protease cathepsin B has been causally linked to progression and metastasis of breast cancers. We demonstrate inhibition by a dipeptidyl nitrile inhibitor (compound 1) of cathepsin B activity and also of pericellular degradation of dye-quenched collagen IV by living breast cancer cells. To image, localize and quantify collagen IV degradation in real-time we used 3D pathomimetic breast cancer models designed to mimic the in vivo microenvironment of breast cancers. We further report the synthesis and characterization of a caged version of compound 1, [Ru(bpy)2(1)2](BF4)2 (compound 2), which can be photoactivated with visible light. Upon light activation, compound 2, like compound 1, inhibited cathepsin B activity and pericellular collagen IV degradation by the 3D pathomimetic models of living breast cancer cells, without causing toxicity. We suggest that caged inhibitor 2 is a prototype for cathepsin B inhibitors that can control both the site and timing of inhibition in cancer.
authors.affiliation: Department of Chemistry, Federal University of São Carlos, São Carlos, São Paulo, Brazil.
authors.forename: Suelem D
authors.initials: SD
authors.lastname: Ramalho
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Rajgopal
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: White
authors.affiliation: Department of Physiology, School of Medicine, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Neha
authors.initials: N
authors.lastname: Aggarwal
authors.affiliation: Department of Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Anita
authors.initials: A
authors.lastname: Chalasani
authors.affiliation: Department of Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Mansoureh
authors.initials: M
authors.lastname: Sameni
authors.affiliation: Department of Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan, United States of America.|Department of Oncology, School of Medicine, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Kamiar
authors.initials: K
authors.lastname: Moin
authors.affiliation: Department of Chemistry, Federal University of São Carlos, São Carlos, São Paulo, Brazil.
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Vieira
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Claudia
authors.initials: C
authors.lastname: Turro
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Kodanko
authors.affiliation: Department of Pharmacology, School of Medicine, Wayne State University, Detroit, Michigan, United States of America.|Department of Oncology, School of Medicine, Wayne State University, Detroit, Michigan, United States of America.
authors.forename: Bonnie F
authors.initials: BF
authors.lastname: Sloane
mesh_terms: D055162:Biocatalysis / Q000187:drug effects; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D024141:Collagen Type IV / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D003952:Diagnostic Imaging / Q000379:methods; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008027:Light; D018613:Microscopy, Confocal; D015394:Molecular Structure; D055668:Photochemical Processes / Q000528:radiation effects; D059748:Proteolysis / Q000187:drug effects; D017975:Ruthenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D024141:Collagen Type IV; D015853:Cysteine Proteinase Inhibitors; D017975:Ruthenium Compounds; D002401:Cathepsin B