title: The activity of a novel mithramycin analog is related to its binding to DNA, cellular accumulation, and inhibition of Sp1-driven gene transcription.
abstract: DIG-MSK (demycarosyl-3D-β-D-digitoxosyl-mithramycin SK) is a recently isolated compound of the mithramycin family of antitumor antibiotics, which includes mithramycin A (MTA) and mithramycin SK (MSK). Here, we present evidence that the binding of DIG-MSK to DNA shares the general features of other mithramycins such as the preference for C/G-rich tracts, but there are some differences in the strength of binding and the DNA sequence preferentially recognized by DIG-MSK. We aimed at gaining further insights into the DIG-MSK mechanism of action by direct comparison with the effects of the parental MTA. Similar to MTA, MSK and DIG-MSK accumulated rapidly in A2780, IGROV1 and OVCAR3 human ovarian cancer cell lines, and DIG-MSK was a potent inhibitor of both basal and induced expression of an Sp1-driven luciferase vector. This inhibitory activity was confirmed for the endogenous Sp1 gene and a set of Sp-responsive genes, and compared to that of MTA and MSK. Furthermore, DIG-MSK was stronger than MTA as inhibitor of Sp3-driven transcription and endogenous Sp3 gene expression. Differences in the effects of MTA, MSK and DIG-MSK on gene expression may have a large influence on their biological activities.
authors.affiliation: Departamento de Biología Funcional, Facultad de Medicina, Universidad de Oviedo, E-33006 Oviedo, Spain.
authors.forename: Azahara
authors.initials: A
authors.lastname: Fernández-Guizán
authors.affiliation: Instituto de Biología Molecular de Barcelona, CSIC, Parc Cientíific de Barcelona, E-08028 Barcelona, Spain.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Mansilla
authors.affiliation: Departament de Biologia Fundamental i Ciencies de la Salut, Universitat de les Illes Balears, E-07122 Palma de Mallorca, Spain.
authors.forename: Francisca
authors.initials: F
authors.lastname: Barceló
authors.affiliation: Instituto de Biología Molecular de Barcelona, CSIC, Parc Cientíific de Barcelona, E-08028 Barcelona, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Vizcaíno
authors.affiliation: EntreChem SL, Edificio Científico Tecnológico, Campus El Cristo, E-33006 Oviedo, Spain.
authors.forename: Luz-Elena
authors.initials: LE
authors.lastname: Núñez
authors.affiliation: EntreChem SL, Edificio Científico Tecnológico, Campus El Cristo, E-33006 Oviedo, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Morís
authors.affiliation: Departamento de Biología Funcional, Facultad de Medicina, Universidad de Oviedo, E-33006 Oviedo, Spain.
authors.forename: Segundo
authors.initials: S
authors.lastname: González
authors.affiliation: Instituto de Biología Molecular de Barcelona, CSIC, Parc Cientíific de Barcelona, E-08028 Barcelona, Spain. Electronic address: jpmbmc@ibmb.csic.es.
authors.forename: José
authors.initials: J
authors.lastname: Portugal
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D007700:Kinetics; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D008926:Plicamycin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D012313:RNA / Q000737:chemistry / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000502:physiology*; D013050:Spectrometry, Fluorescence; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D000903:Antibiotics, Antineoplastic; D058851:GPI-Linked Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016329:Sp1 Transcription Factor; C423231:ULBP1 protein, human; C576677:demycarosyl-3D-digitoxosylmithramycin SK; D012313:RNA; D008926:Plicamycin
keywords: Cell Uptake; DNA-binding; Mithramycin; Ovarian cancer; Transcription