title: The UVB1 Vitamin D analogue inhibits colorectal carcinoma progression.
abstract: Vitamin D has been shown to display a wide variety of antitumour effects, but their therapeutic use is limited by its severe side effects. We have designed and synthesized a Gemini vitamin D analogue of calcitriol (UVB1) which has shown to display antineoplastic effects on different cancer cell lines without causing hypercalcemia. The aim of this work has been to investigate, by employing in silico, in vitro, and in vivo assays, whether UVB1 inhibits human colorectal carcinoma progression. We demonstrated that UVB1 induces apoptotic cell death and retards cellular migration and invasion of HCT116 colorectal carcinoma cells. Moreover, the analogue reduced the tumour volume in vivo, and modulated the expression of Bax, E-cadherin and nuclear β-catenin in tumour animal tissues without producing toxic effects. In silico analysis showed that UVB1 exhibits greater affinity for the ligand binding domain of vitamin D receptor than calcitriol, and that several characteristics in the three-dimensional conformation of VDR may influence the biological effects. These results demonstrate that the Gemini vitamin D analogue affects the growth of the colorectal cancer and suggest that UVB1 is a potential chemotherapeutic agent for treatment of this disease.
authors.affiliation: Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca (INIBIBB), Centro Científico Tecnológico Bahía Blanca (CONICET-UNS), Bahía Blanca, Argentina.
authors.forename: María Julia
authors.initials: MJ
authors.lastname: Ferronato
authors.affiliation: Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca (INIBIBB), Centro Científico Tecnológico Bahía Blanca (CONICET-UNS), Bahía Blanca, Argentina.
authors.forename: Eliana Noelia
authors.initials: EN
authors.lastname: Alonso
authors.affiliation: Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca (INIBIBB), Centro Científico Tecnológico Bahía Blanca (CONICET-UNS), Bahía Blanca, Argentina.
authors.forename: Norberto Ariel
authors.initials: NA
authors.lastname: Gandini
authors.affiliation: Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca (INIBIBB), Centro Científico Tecnológico Bahía Blanca (CONICET-UNS), Bahía Blanca, Argentina.
authors.forename: María Eugenia
authors.initials: ME
authors.lastname: Fermento
authors.affiliation: Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca (INIBIBB), Centro Científico Tecnológico Bahía Blanca (CONICET-UNS), Bahía Blanca, Argentina.
authors.forename: María Emilia
authors.initials: ME
authors.lastname: Villegas
authors.affiliation: Unidad de Investigación y Desarrollo en Tecnología Farmacéutica (UNITEFA-CONICET), Facultad de Ciencias Químicas, Ciudad Universitaria, Universidad Nacional de Córdoba, 5000 Córdoba, Argentina.
authors.forename: Mario Alfredo
authors.initials: MA
authors.lastname: Quevedo
authors.affiliation: Servicio de Patología del Hospital Interzonal General de Agudos Dr. José Penna, Av. Láinez 2401, 8000 Bahía Blanca, Argentina.
authors.forename: Julián
authors.initials: J
authors.lastname: Arévalo
authors.affiliation: Departamento de Hematología, Laboratorios IACA, Bahía Blanca, Argentina.
authors.forename: Alejandro
authors.initials: A
authors.lastname: López Romero
authors.affiliation: Departamento de Química Orgánica, Facultad de Química and Instituto de Investigación Biomédica (IBI), University of Vigo, Campus Lagoas de Marcosende, 36310 Vigo, Spain.
authors.forename: Marcos Lois
authors.initials: ML
authors.lastname: Rivadulla
authors.affiliation: Departamento de Química Orgánica, Facultad de Química and Instituto de Investigación Biomédica (IBI), University of Vigo, Campus Lagoas de Marcosende, 36310 Vigo, Spain.
authors.forename: Generosa
authors.initials: G
authors.lastname: Gómez
authors.affiliation: Departamento de Química Orgánica, Facultad de Química and Instituto de Investigación Biomédica (IBI), University of Vigo, Campus Lagoas de Marcosende, 36310 Vigo, Spain.
authors.forename: Yagamare
authors.initials: Y
authors.lastname: Fall
authors.affiliation: Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca (INIBIBB), Centro Científico Tecnológico Bahía Blanca (CONICET-UNS), Bahía Blanca, Argentina.
authors.forename: María Marta
authors.initials: MM
authors.lastname: Facchinetti
authors.affiliation: Laboratorio de Biología del Cáncer, Instituto de Investigaciones Bioquímicas Bahía Blanca (INIBIBB), Centro Científico Tecnológico Bahía Blanca (CONICET-UNS), Bahía Blanca, Argentina. Electronic address: acurino@criba.edu.ar.
authors.forename: Alejandro Carlos
authors.initials: AC
authors.lastname: Curino
mesh_terms: D000818:Animals; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; C494826:BAX protein, human; C513384:CDH1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D008024:Ligands; D018167:Receptors, Calcitriol; C000604793:UVB1 compound; C579457:VDR protein, human; D051028:bcl-2-Associated X Protein; D051176:beta Catenin; D014807:Vitamin D
keywords: Analogue; Calcitriol; Colorectal cancer; Gemini; Vitamin D