G-quadruplex, Friend or Foe: The Role of the G-quartet in Anticancer Strategies

The clinical applicability of G-quadruplexes (G4s) as anticancer drugs is currently being evaluated. Several G4 ligands and aptamers are undergoing clinical trials following the notable examples of quarfloxin and AS1411, respectively. In this review, we summarize the latest achievements and breakthroughs in the use of G4 nucleic acids as both therapeutic tools (‘friends’, as healing anticancer drugs) and targets (‘foes’, within the harmful cancer cell), particularly using aptamers and quadruplex-targeted ligands, respectively. We explore the recent research on synthetic G4 ligands toward the discovery of anticancer therapeutics and their mechanism of action. Additionally, we highlight recent advances in chemical and structural biology that enable the design of specific G4 aptamers to be used as novel anticancer agents. Guanine-rich sequences with the potential to form stable G4 structures are nonrandomly distributed throughout the human genome, being over-represented in key regions, such as telomeres, gene promoters, and RNA molecules.Current evidence points to the clinical relevance of G4s, particularly in anticancer drug design. Small compounds able to bind and stabilize these structures have been synthesized and their potential to interfere with telomeric functions and/or oncogene expression has been demonstrated.G4s constitute a motif frequently found in aptamers (i.e., synthetic nucleic acids resulting from an in vitro selection process against a target, such as nucleolin). Several aptamers are guanine-rich G4-forming sequences that target proteins with remarkable biological effects.