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The activity of a novel mithramycin analog is related to its binding to DNA, cellular accumulation, and inhibition of Sp1-driven gene transcription

AuthorsFernández-Guizán, Azahara; Mansilla, Sylvia ; Barceló, Francisca; Vizcaíno, Carolina ; Núñez, Luz-Elena; Morís, Francisco; González, Segundo; Portugal, José
KeywordsCell Uptake
Ovarian cancer
Issue Date5-Aug-2014
CitationChemico-Biological Interactions 219: 123-132 (2014)
AbstractDIG-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. © 2014 Elsevier Ltd. All rights reserved.
Publisher version (URL)http://dx.doi.org/10.1016/j.cbi.2014.05.019
Identifiersdoi: 10.1016/j.cbi.2014.05.019
issn: 1872-7786
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