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

被引：32

作者：

Fernandez-Guizan, Azahara ^{[1
]}

Mansilla, Sylvia ^{[2
]}

Barcelo, Francisca ^{[3
]}

Vizcaino, Carolina ^{[2
]}

Nunez, Luz-Elena ^{[4
]}

Moris, Francisco ^{[4
]}

Gonzalez, Segundo ^{[1
]}

Portugal, Jose ^{[2
]}

机构：

[1] Univ Oviedo, Fac Med, Dept Biol Func, E-33006 Oviedo, Spain

[2] CSIC, Inst Biol Mol Barcelona, E-08028 Barcelona, Spain

[3] Univ Illes Balears, Dept Biol Fundamental & Ciencies Salut, E-07122 Palma De Mallorca, Spain

[4] EntreChem SL, E-33006 Oviedo, Spain

来源：

CHEMICO-BIOLOGICAL INTERACTIONS | 2014年 / 219卷

关键词：

Cell Uptake; DNA-binding; Mithramycin; Ovarian cancer; Transcription; PRODUCER STREPTOMYCES-ARGILLACEUS; COMBINATORIAL BIOSYNTHESIS; OVARIAN-CANCER; ANTITUMOR-ACTIVITY; NKG2D LIGANDS; TUMOR-CELLS; EXPRESSION; SP1; PROMOTER; FAMILY;

D O I：

10.1016/j.cbi.2014.05.019

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

DIG-MSK (demycarosyl-3D-beta-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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.

引用

页码：123 / 132

页数：10

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