title: A metal-containing nucleoside that possesses both therapeutic and diagnostic activity against cancer.
abstract: Nucleoside transport is an essential process that helps maintain the hyperproliferative state of most cancer cells. As such, it represents an important target for developing diagnostic and therapeutic agents that can effectively detect and treat cancer, respectively. This report describes the development of a metal-containing nucleoside designated Ir(III)-PPY nucleoside that displays both therapeutic and diagnostic properties against the human epidermal carcinoma cell line KB3-1. The cytotoxic effects of Ir(III)-PPY nucleoside are both time- and dose-dependent. Flow cytometry analyses validate that the nucleoside analog causes apoptosis by blocking cell cycle progression at G2/M. Fluorescent microscopy studies show rapid accumulation in the cytoplasm within 4 h. However, more significant accumulation is observed in the nucleus and mitochondria after 24 h. This localization is consistent with the ability of the metal-containing nucleoside to influence cell cycle progression at G2/M. Mitochondrial depletion is also observed after longer incubations (Δt ∼48 h), and this effect may produce additional cytotoxic effects. siRNA knockdown experiments demonstrate that the nucleoside transporter, hENT1, plays a key role in the cellular entry of Ir(III)-PPY nucleoside. Collectively, these data provide evidence for the development of a metal-containing nucleoside that functions as a combined therapeutic and diagnostic agent against cancer.
authors.affiliation: From the Department of Chemistry and the Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, Ohio 44115 and.
authors.forename: Jung-Suk
authors.initials: JS
authors.lastname: Choi
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Ayan
authors.initials: A
authors.lastname: Maity
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gray
authors.affiliation: From the Department of Chemistry and the Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, Ohio 44115 and a.berdis@csuohio.edu.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Berdis
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007495:Iridium / Q000378:metabolism; D008670:Metals / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D009336:Necrosis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009705:Nucleosides / Q000378:metabolism* / Q000494:pharmacology*; D034622:RNA Interference; D013997:Time Factors
chemical_list: D033721:Equilibrative Nucleoside Transporter 1; D008670:Metals; D009705:Nucleosides; C438649:SLC29A1 protein, human; D007495:Iridium
keywords: Cancer Therapy; Molecular Imaging; Molecular Pharmacology; Nucleoside/Nucleotide Analogue; Transport