Pleiotropic Anti-Angiogenic and Anti-Oncogenic Activities of the Novel Mithralog Demycarosyl-3D-ß-D-Digitoxosyl-Mithramycin SK (EC-8042)

PLoS One. 2015 Nov 4;10(11):e0140786. doi: 10.1371/journal.pone.0140786. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inducing Agents / metabolism
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / toxicity*
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Female
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Leukocytes, Mononuclear / cytology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Neovascularization, Physiologic / drug effects
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Plicamycin / analogs & derivatives*
  • Plicamycin / chemistry
  • Plicamycin / toxicity
  • Vascular Endothelial Growth Factor Receptor-1 / genetics
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / genetics
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Angiogenesis Inducing Agents
  • Antineoplastic Agents
  • demycarosyl-3D-digitoxosylmithramycin SK
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factor Receptor-2
  • Plicamycin

Grants and funding

This work has been funded by the grant PI12/01280 from the Instituto de Salud Carlos III and the FEDER program of the European Community. It was also supported by the Principado de Asturias Government through PCTI funds 2006-2009, co-financed with the FEDER Operative Program of the Principado de Asturias 2007-2013 (project FC-11-PC-10-31). A.L.S. holds a Sara Borrell fellowship from the Instituto de Salud Carlos III. The drugs MTA and DIG-MSK were provided by the company EntreChem (http://entrechem.com/es/about_us/index.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. EntreChem provided support in the form of salaries for authors LEN and FM, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.