Challenging transcription by DNA-binding antitumor drugs

Abstract Cancer has been associated with altered gene expression. Therefore, transcription and its regulation by transcription factors are considered key points to be explored in the pursuit of more efficient antitumor agents. This paper reviews the effects of DNA-binding drugs on the interaction between transcription factors and DNA, and it discusses recent advances in the understanding of the mechanisms by which small compounds interfere with the activity of transcription factors and gene expression. Many DNA-binding drugs, some of them in clinical use, can compete with a variety of transcription factors for their preferred binding sites in gene promoters, or they can covalently modify DNA, thus preventing transcription factors from recognizing their binding sites. On the other hand, transcription factor activity can be impaired through modification of the protein factors or their complexes. Several “omic” tools have been developed to explore the genome-wide changes in gene expression induced by DNA-binding drugs, which reveal details of the mechanisms of action. Transcriptomic profiles obtained from drug-treated cells and of samples collected from patients upon treatment provide insights into the in vivo mechanisms of drug action related to the inhibition of gene transcription. The information available about the molecular structure and mechanisms of action of both transcription factors and DNA-binding drugs, together with the new opportunities provided by functional genomics, should encourage the development of new more-selective DNA-binding antitumor drugs to target a single gene with little effect on others.