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.
Highlights
Ovarian cancer is an important cause of morbidity and mortality worldwide and the main cause of death among gynecological cancers [1,2]
digitoxosyl mithramycin SK (DIG-MSK) inhibits the proliferation of A2780 human ovarian carcinoma cells
We have presented a genome-wide analysis probing the ‘‘anti-transcriptional’’ properties of the novel mithramycin analogue DIG-MSK, which had shown a promising in vivo antitumor profile [25]
Summary
Ovarian cancer is an important cause of morbidity and mortality worldwide and the main cause of death among gynecological cancers [1,2]. An integrated genomic analysis has been undertaken [6], and there have been intents to assess the association between transcription, overall survival and response to chemotherapy [7,8]. In this context, identifying transcription factors that are involved in tumorigenesis and cancer progression may provide us with targets for chemotherapeutic intervention based on small compounds [5,9]. These genes are activated by Sp1 [16,17,18] and/or by other transcription factors [7], representing potential targets for therapeutic intervention
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
