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Genome-wide modulation of gene transcription in ovarian carcinoma cells by a new mithramycin analogue.

Vizcaíno C, Núñez LE, Morís F, Portugal J - PLoS ONE (2014)

Bottom Line: Nanomolar concentrations of DIG-MSK abrogated the expression of genes involved in a variety of cell processes including transcription regulation and tumor development, which resulted in cell death.The effect of DIG-MSK in the control of gene expression by other transcription factors was also explored.DIG-MSK affected several biological processes and molecular functions related to transcription and its cellular regulation in A2780 cells, including transcription factor activity.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Cientificas, Barcelona, Spain.

ABSTRACT
Ovarian cancer has a poor prognosis due to intrinsic or acquired resistance to some cytotoxic drugs, raising the interest in new DNA-binding agents such as mithramycin analogues as potential chemotherapeutic agents in gynecological cancer. Using a genome-wide approach, we have analyzed gene expression in A2780 human ovarian carcinoma cells treated with the novel mithramycin analogue DIG-MSK (demycarosyl-3D-β-D-digitoxosyl-mithramycin SK) that binds to C+G-rich DNA sequences. Nanomolar concentrations of DIG-MSK abrogated the expression of genes involved in a variety of cell processes including transcription regulation and tumor development, which resulted in cell death. Some of those genes have been associated with cell proliferation and poor prognosis in ovarian cancer. Sp1 transcription factor regulated most of the genes that were down-regulated by the drug, as well as the up-regulation of other genes mainly involved in response to cell stress. The effect of DIG-MSK in the control of gene expression by other transcription factors was also explored. Some of them, such as CREB, E2F and EGR1, also recognize C/G-rich regions in gene promoters, which encompass potential DIG-MSK binding sites. DIG-MSK affected several biological processes and molecular functions related to transcription and its cellular regulation in A2780 cells, including transcription factor activity. This new compound might be a promising drug for the treatment of ovarian cancer.

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Related in: MedlinePlus

Chemical formulae of the mithramycin analogue DIG-MSK (demycarosyl-3D-β-D-digitoxosyl-mithramycin SK).DIG-MSK differs from the parental mithramycin A in the side chain linked to C-3 and the distal sugar in the trisaccharide moiety.
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pone-0104687-g001: Chemical formulae of the mithramycin analogue DIG-MSK (demycarosyl-3D-β-D-digitoxosyl-mithramycin SK).DIG-MSK differs from the parental mithramycin A in the side chain linked to C-3 and the distal sugar in the trisaccharide moiety.

Mentions: The genetic organization of the MTA biosynthesis gene cluster has been studied in detail, and the MTA biosynthetic pathway used to produce new compounds with enhanced biological characteristics [19], [21], [24]–[26]. New mithramycin analogues bearing both lower toxicity and higher biological activity are now available, providing new possibilities for therapeutic application [18], [19], [25]. MTA and its analogues tested to date can inhibit transcription both in vivo and in vitro by interfering with protein-DNA interactions, especially the inhibition of Sp1-dependent transcription [17], [18], [27]–[29]. Recently, a new analogue named DIG-MSK (demycarosyl-3D-β-D-digitoxosyl-mithramycin SK; EC-8042) (Fig. 1) has been obtained and characterized [25]. DIG-MSK shows in vivo and in vitro antitumor activities similar to other novel analogues like the structurally related MSK, but DIG-MSK is 10-fold less toxic in vivo than MTA and 25% less toxic than MSK [25]. Remarkably, the single maximum tolerated dose of DIG-MSK in mice is the highest among the mithramycin analogues [25]. DIG-MSK inhibits the growth of HCT-116 human colon carcinoma cells, where it inhibits the interaction between transcription factors and DNA [29]. Moreover, the in vivo evaluation of DIG-MSK antitumor activity by hollow fiber assays indicates that it is a promising antitumor drug against ovarian cancer, among other neoplasms [25].


Genome-wide modulation of gene transcription in ovarian carcinoma cells by a new mithramycin analogue.

Vizcaíno C, Núñez LE, Morís F, Portugal J - PLoS ONE (2014)

Chemical formulae of the mithramycin analogue DIG-MSK (demycarosyl-3D-β-D-digitoxosyl-mithramycin SK).DIG-MSK differs from the parental mithramycin A in the side chain linked to C-3 and the distal sugar in the trisaccharide moiety.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128730&req=5

pone-0104687-g001: Chemical formulae of the mithramycin analogue DIG-MSK (demycarosyl-3D-β-D-digitoxosyl-mithramycin SK).DIG-MSK differs from the parental mithramycin A in the side chain linked to C-3 and the distal sugar in the trisaccharide moiety.
Mentions: The genetic organization of the MTA biosynthesis gene cluster has been studied in detail, and the MTA biosynthetic pathway used to produce new compounds with enhanced biological characteristics [19], [21], [24]–[26]. New mithramycin analogues bearing both lower toxicity and higher biological activity are now available, providing new possibilities for therapeutic application [18], [19], [25]. MTA and its analogues tested to date can inhibit transcription both in vivo and in vitro by interfering with protein-DNA interactions, especially the inhibition of Sp1-dependent transcription [17], [18], [27]–[29]. Recently, a new analogue named DIG-MSK (demycarosyl-3D-β-D-digitoxosyl-mithramycin SK; EC-8042) (Fig. 1) has been obtained and characterized [25]. DIG-MSK shows in vivo and in vitro antitumor activities similar to other novel analogues like the structurally related MSK, but DIG-MSK is 10-fold less toxic in vivo than MTA and 25% less toxic than MSK [25]. Remarkably, the single maximum tolerated dose of DIG-MSK in mice is the highest among the mithramycin analogues [25]. DIG-MSK inhibits the growth of HCT-116 human colon carcinoma cells, where it inhibits the interaction between transcription factors and DNA [29]. Moreover, the in vivo evaluation of DIG-MSK antitumor activity by hollow fiber assays indicates that it is a promising antitumor drug against ovarian cancer, among other neoplasms [25].

Bottom Line: Nanomolar concentrations of DIG-MSK abrogated the expression of genes involved in a variety of cell processes including transcription regulation and tumor development, which resulted in cell death.The effect of DIG-MSK in the control of gene expression by other transcription factors was also explored.DIG-MSK affected several biological processes and molecular functions related to transcription and its cellular regulation in A2780 cells, including transcription factor activity.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Cientificas, Barcelona, Spain.

ABSTRACT
Ovarian cancer has a poor prognosis due to intrinsic or acquired resistance to some cytotoxic drugs, raising the interest in new DNA-binding agents such as mithramycin analogues as potential chemotherapeutic agents in gynecological cancer. Using a genome-wide approach, we have analyzed gene expression in A2780 human ovarian carcinoma cells treated with the novel mithramycin analogue DIG-MSK (demycarosyl-3D-β-D-digitoxosyl-mithramycin SK) that binds to C+G-rich DNA sequences. Nanomolar concentrations of DIG-MSK abrogated the expression of genes involved in a variety of cell processes including transcription regulation and tumor development, which resulted in cell death. Some of those genes have been associated with cell proliferation and poor prognosis in ovarian cancer. Sp1 transcription factor regulated most of the genes that were down-regulated by the drug, as well as the up-regulation of other genes mainly involved in response to cell stress. The effect of DIG-MSK in the control of gene expression by other transcription factors was also explored. Some of them, such as CREB, E2F and EGR1, also recognize C/G-rich regions in gene promoters, which encompass potential DIG-MSK binding sites. DIG-MSK affected several biological processes and molecular functions related to transcription and its cellular regulation in A2780 cells, including transcription factor activity. This new compound might be a promising drug for the treatment of ovarian cancer.

Show MeSH
Related in: MedlinePlus