G-quadruplexes: a promising target for cancer therapy

Abstract

DNA and RNA can fold into a variety of alternative conformations. In recent years, a particular nucleic acid structure was discussed to play a role in malignant transformation and cancer development. This structure is called a G-quadruplex (G4). G4 structure formation can drive genome instability by creating mutations, deletions and stimulating recombination events. The importance of G4 structures in the characterization of malignant cells was currently demonstrated in breast cancer samples. In this analysis a correlation between G4 structure formation and an increased intratumor heterogeneity was identified. This suggests that G4 structures might allow breast cancer stratification and supports the identification of new personalized treatment options. Because of the stability of G4 structures and their presence within most human oncogenic promoters and at telomeres, G4 structures are currently tested as a therapeutic target to downregulate transcription or to block telomere elongation in cancer cells. To date, different chemical molecules (G4 ligands) have been developed that aim to target G4 structures. In this review we discuss and compare G4 function and relevance for therapeutic approaches and their impact on cancer development for three cancer entities, which differ significantly in their amount and type of mutations: pancreatic cancer, leukemia and malignant melanoma. G4 structures might present a promising new strategy to individually target tumor cells and could support personalized treatment approaches in the future.

On the Road to Fight Cancer: The Potential of G-Quadruplex Ligands as Novel Therapeutic Agents

“…In the present review we have provided, without demanding completeness, a brief overlook on the potential of G4 ligands as therapeutic agents in cancer ( Table 1 ). In particular, we draw the readers’ attention to few examples that have been paradigmatic to depict how small molecule-mediated stabilization of G4 structures may represent an intriguing strategy that could be implemented in the fight of cancer [ 14 , 15 , 16 , 17 , 18 , 29 ].…”

“…The variety of small molecules evaluated for their G4 stabilizing properties is countless [ 34 ]. Most of them have been reported to exert a remarkable antiproliferative activity accompanied, in some cases, by evidence of pharmacodynamic activity, when used as single agents in several in vitro models of human cancers [ 2 , 12 , 14 , 15 , 16 , 17 , 18 , 29 , 57 , 63 ]. Moreover, synergistic pharmacological interactions have been also documented for some G4 ligands when combined to conventional anticancer therapies [ 12 , 14 ], both in vitro and in vivo.…”

“…It has been also reported that compounds with reduced planarity (i.e., lacking the flat aromatic core) may be amenable of G4 targeting through the interaction with the grooves and/or the nucleic acid backbone [ 33 ]. To date, several small molecules belonging to distinct chemical families have been designed and characterized as G4 ligands [ 34 ] and a subset of them have been evaluated for their therapeutic potential in cancer [ 14 , 15 , 16 , 17 , 18 , 29 ].…”

“…As originally outlined by Brooks et al [ 13 ], it is now possible to catalog several tumor-associated genes, the promoter of which may harbor G4 forming sequences [ 13 , 14 , 15 ]. Consequently, in the perspective of antitumor therapeutic strategies, the selective stabilization of G4 within gene regulatory elements by small-molecules has appeared as a suitable tool to operate at genomic level for the control of aberrant gene expression [ 15 , 16 , 17 , 18 ]. This notion has gained support by data showing that the G4 ligand pyridostatin (PDS) was able to inhibit gene expression by interacting with quadruplex-forming sequences within the human genome [ 19 ].…”

Exploring New Potential Anticancer Activities of the G-Quadruplexes Formed by [(GTG2T(G3T)3] and Its Derivatives with an Abasic Site Replacing Single Thymidine

“…G-quadruplexes occur naturally in telomers, as well as in promoter regions. Many regulators of transcription, translation, replication, signal transduction, recombination, and other key biological processes in cells are cellular proteins that specifically interact with these non-canonical structures [4][5][6]. Consequently, exogenous G4 aptamers can affect the activity of G4-recognizing proteins, constituting one of the most investigated classes of protein ligands of considerable relevance in research areas such as diagnostics, therapeutics, biosensing, or gene silencing.…”