G-quadruplexes: targets and tools in anticancer drug design

Abstract

Background: Guanosine (G)-rich DNA and RNA sequences can adopt a defined secondary structure, the G-quadruplex, which consists of multiple stacked G-tetrads. Each G-tetrad has four Gs arranged in a planar configuration and held together by hydrogen bonding. G-quadruplexes are found in chromosomal DNA and RNA transcripts, particularly in telomeric sequences, and in regulatory regions of many genes including oncogenes.Purpose: This review summarizes how G-quadruplexes can be employed for anticancer therapies and discusses possible mechanisms. Methods: The Medline database was searched using the terms “G-rich oligonucleotide (GRO)”, “G-tetrad”, and “G-quadruplex”.Results: Drugs which bind to and stabilize G-quadruplexes can be employed to suppress the elongation of telomers and the gene transcription and translation of oncogenes. G-quadruplex stabilization results in senescence and apoptosis of cancer cells. Besides long-chain nucleic acids, also GRO are able to acquire G-quadruplex conformation to build up a variety of stable structures. Selected aptamers show a highly specific binding capacity to their target molecules, similar to antibodies. Some GRO were shown to induce cell death, preferentially in cancer cells; they demonstrated remarkable anticancer activity in preclinical and first clinical studies.Conclusion: G-quadruplexes can be both, targets and tools in anticancer drug development.