title: Pleiotropic Anti-Angiogenic and Anti-Oncogenic Activities of the Novel Mithralog Demycarosyl-3D-ß-D-Digitoxosyl-Mithramycin SK (EC-8042).
abstract: Demycarosyl-3D-ß-D-digitoxosyl-mithramycin SK (DIG-MSK) is a recently isolated analogue of mithramycin A (MTA) that showed differences with MTA in the DNA binding strength and selectivity. These differences correlated with a better therapeutic index and less toxicity in animal studies. Herein, we show that DIG-MSK displays a potent anti-tumor activity against different types of cancer cell lines, ovarian tumor cells being particularly sensitive to this drug. Of relevance, DIG-MSK exerts low toxicity on fibroblasts and peripheral blood mononuclear cells, this toxicity being significantly lower than that of MTA. In correlation with its antitumor activity, DIG-MSK strongly inhibited Sp1-mediated transcription and endogenous Sp1 mRNA expression, which correlated with the inhibition of the expression of key Sp1-regulated genes involved in tumorigenesis, including VEGFA, BCL2L1 (Bcl-XL), hTERT, BRCA2, MYC and SRC in several ovarian cells. Significantly, DIG-MSK was a stronger inhibitor of VEGFA expression than MTA. Accordingly, DIG-MSK also exhibited potent anti-angiogenic activity on microvascular endothelial cells. Likewise, it significantly inhibited the gene expression of VEGFR1, VEGFR2, FGFR, PDGFB and PDGFRA and, additionally, it induced the expression of the anti-angiogenic factors angiostatin and tunstatin. These effects correlated with a pro-apoptotic effect on proliferating microvascular endothelial cells and the inhibition of the formation of endothelial capillary structures. Overall, the pleiotropic activity of DIG-MSK in inhibiting key oncogenic and angiogenic pathways, together with its low toxicity profile, highlight the therapeutic potential of this new drug.
authors.affiliation: Department of Functional Biology, IUOPA, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Azahara
authors.initials: A
authors.lastname: Fernández-Guizán
authors.affiliation: Department of Functional Biology, IUOPA, Universidad de Oviedo, Oviedo, Spain.|Department of Immunology, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: López-Soto
authors.affiliation: Department of Functional Biology, IUOPA, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Andrea
authors.initials: A
authors.lastname: Acebes-Huerta
authors.affiliation: Department of Functional Biology, IUOPA, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: Huergo-Zapico
authors.affiliation: Department of Functional Biology, IUOPA, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Villa-Álvarez
authors.affiliation: EntreChem S.L., Campus El Cristo, 33006-Oviedo, Spain.
authors.forename: Luz-Elena
authors.initials: LE
authors.lastname: Núñez
authors.affiliation: EntreChem S.L., Campus El Cristo, 33006-Oviedo, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Morís
authors.affiliation: Department of Functional Biology, IUOPA, Universidad de Oviedo, Oviedo, Spain.
authors.forename: Segundo
authors.initials: S
authors.lastname: Gonzalez
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D008926:Plicamycin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D000970:Antineoplastic Agents; C576677:demycarosyl-3D-digitoxosylmithramycin SK; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D008926:Plicamycin