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

AuthorsVizcaíno, Carolina ; Núñez, Luz-Elena; Morís, Francisco; Portugal, José
Issue Date5-Oct-2015
CitationInternational Summer School - Plant Derived Polyphenols as Drug Leads (2015)
AbstractOvarian cancer is an important cause of morbidity and mortality worldwide and the main cause of death among gynecological cancers. Despite improvements in complete clinical remission and progression-free survival, resistance to chemotherapy presents a major problem in the treatment and a contributing factor in cancer-associated mortality. Therefore, given that ovarian cancer shows a high risk of relapse, it seems necessary to improve the efficacy of novel targeted therapies. Regulation of gene transcription is often a central point in oncogenic signaling. In ovarian cancer, an integrated genomic analysis has been undertaken, and there have been intents to assess the association between transcription, overall survival and response to chemotherapy. Although targeting transcription factors and their interactions with gene promoters is a difficult approach, it is nowadays considered an attainable goal. In fact, many clinically useful agents, such as the anthracyclines, several alkylating agents and mithramycin A (MTA), can regulate gene expression by binding to C+G-rich DNA sequences recognized by the Sp-family of transcription factors, thus abrogating the transcriptional activity of genes essential for cancer cell growth. In many cases, these genes are activated by Sp1 and/or by other transcription factors, representing potential targets for therapeutic intervention. New mithramycin analogues bearing both lower toxicity and higher biological activity are now available. MTA and its analogues tested to date can inhibit transcription both in vivo and in vitro by interfering with protein-DNA interactions. Recently, a new analogue named DIG-MSK (demycarosyl-3D-b-D-digitoxosyl-mithramycin SK; EC-8042) 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.
DescriptionTrabajo presentado en la International Summer School - Plant Derived Polyphenols as Drug Leads, celebrada en Alemania, del 3 al 10 de octubre de 2015
Appears in Collections:(IBMB) Comunicaciones congresos
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