ReviewKeynoteG-Quadruplex surveillance in BCL-2 gene: a promising therapeutic intervention in cancer treatment

•The atomic-level structures of G-quadruplexes in BCL-2 promoter/transcripts are described.•G-quadruplexes contribute to cellular processes and oncogenic transformation of BCL-2.•Recent pharmacological advances in quadruplex-targeting molecules are discussed.•Quadruplex-based therapy overcomes the limitations of BCL-2 protein-based therapy.•The promises and challenges of BCL-2 quadruplex-based therapies are examined.BCL-2 overexpression promotes neoplastic cell expansion in cancers. Multiple noncanonical B-DNA motifs in the BCL-2 gene regulate selective modulation of its expression in normal and cancer cells. Three G-quadruplex topologies and one i-motif, in the vicinity of the P1 (major) promoter, stringently control its transcription. RNA quadruplexes and Z-DNA elements within translocation breakpoints of noncoding regions affect translation and promote oncogenic transformation of BCL-2 [e.g., t(14;18) translocation]. These structures, therefore, suggest promising targets in gene-directed anticancer therapeutics. This review summarizes structural and mechanistic aspects of G-quadruplexes, and recent pharmacological advances in BCL-2-quadruplex-targeted drug design together with prospects and challenges in cancer treatment.