Effects of anticancer drugs on transcription factor–DNA interactions

Abstract

DNA-interacting anticancer drugs are able to affect the propensity of DNA to interact with proteins through either reversible binding or covalent bond formation. The effect of the drugs on transcription factor interactions with DNA is reviewed. These effects can be classified as (i) competition between a drug and regulatory protein for target sequences; (ii) weakening of this interaction; (iii) enhancement of this interaction by chemical modification of the DNA and the creation of non-natural binding sites; and (iv) a 'suicide' mechanism, which is observed when a transcription factor induces changes in DNA structure, allowing a drug to bind to a target sequence. Several new strategies -- the antigene approach with oligonucleotides, peptide nucleic acids or locked nucleic acids, and sequence-specific polyamides -- are also reviewed.

Sp1 transcription factor: A long-standing target in cancer chemotherapy

“…Several compounds displaying sequence selectivity in their binding to DNA can exhibit differential effects on the interactions between DNA and DNA-binding proteins, which includes the members of the Sp-family (Chiang, et al, 1998;Gniazdowski, et al, 2005;Hurley, 2002;Lee, et al, 2009;Mansilla & Portugal, 2008;Minuzzo, et al, 2000;Portugal, et al, 2011;Snyder, et al, 1991). The clinical success as antitumor drugs of a number of DNA-binding chemotherapeutic agents is ascribed, at least in part, to their capacity for inhibiting transcription (Gniazdowski, et al, 2005;Hurley, 2002;Portugal, et al, 2011).…”

“…Therefore, DNA-binding drugs are considered potential agents aimed at inhibiting unpaired transcription that could prevail in several pathologies, including cancer (Gniazdowski, et al, 2005;Hurley, 2002;Portugal, et al, 2011). It is worth noting that the foremost mechanism of action of many of the first-line cytotoxic agents already approved by for clinical usage, including DNA-alkylating agents and the anthracyclines, is the ability to inhibit transcription (Gniazdowski, et al, 2005;Portugal, et al, 2011).…”

“…Therefore, DNA-binding drugs are considered potential agents aimed at inhibiting unpaired transcription that could prevail in several pathologies, including cancer (Gniazdowski, et al, 2005;Hurley, 2002;Portugal, et al, 2011). It is worth noting that the foremost mechanism of action of many of the first-line cytotoxic agents already approved by for clinical usage, including DNA-alkylating agents and the anthracyclines, is the ability to inhibit transcription (Gniazdowski, et al, 2005;Portugal, et al, 2011). However, there are only a few examples of molecules developed to target the dysregulation of transcription, and despite challenges involved in making molecules aimed at targeting transcription factors, there are grounds for considering that this approach is a highly promising strategy in the development of cancer treatments (Frank, 2009;Yan & Higgins, 2013).…”

Evaluation of flavonoids binding to DNA duplexes by electrospray ionization mass spectrometry

“…. These drugs may bind to certain DNA sequences, prevent the specific recognition of these sequences with their trans-acting factors, and interfere with the replication or transcription of certain genes, and thus exert their pharmacological activities [2]. Among the various organic molecules, natural products have attracted considerable interest given that many clinical anticancer drugs are natural products (or their derivatives) and most of them exert their effects by acting on DNA [1].…”

Peptide scalpels for site-specific dissection of the DNA–protein interface

“…Conjugation with a natural alkylating moiety, like CC-1065 or duocarmycin, enhances the efficiency and selectivity of the DNA alkylation and can be used for gene silencing, as alkylated coding regions cannot be read by RNA polymerase II [19,20]. Except for the TATA box binding protein, most natural proteins bind in the major groove.…”