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.
Highlights
Induction of angiogenesis is a hallmark of the tumorigenic process that plays a key role in tumor progression and metastasis [1]
We showed that digitoxosyl-mithramycin SK (DIG-MSK) is as efficient as mithramycin A (MTA) in inhibiting Sp1 function, but it differs from MTA in the strength and selectivity of DNA binding [12]
The effect of MTA and DIG-MSK on the viability of a panel of cell lines was analyzed by determining the drug concentrations required for inhibiting cell viability by 50% (IC50) [19]
Summary
Induction of angiogenesis is a hallmark of the tumorigenic process that plays a key role in tumor progression and metastasis [1]. Cancer cells secrete pro-angiogenic factors that stimulate capillary growth into the tumor bed. Vascular endothelial growth factor (VEGF) is a crucial angiogenic factor that comprises two structurally and functionally related proteins termed VEGFA and VEGFB, being VEGFA the dominant angiogenic factor in most settings [2,3]. A redundant number of angiogenic factors, including angiopoietins, platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF), collaborate with VEGF in the angiogenic process [4]. Many tumors sooner or later become refractory or resistant to VEGF blockade. This resistance is frequently caused by the activation of alternative angiogenic proteins, such as FGFs, due to preexisting multiple redundant pro-angiogenic molecules and pathways [5,6,8]
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