Antimalarial Drugs Induce the Selective Folding of Human Telomeric G-Quadruplex in a Cancer-Mimicking Microenvironment

Regulating the equilibrium between the duplex form ofDNA and G-quadruplex(Gq) and stabilizing the folded Gq are the critical factors for anydrug to be effective in cancer therapy due to the direct involvementof Gq in controlling the transcription process. Antimalarial drugsare in the trial stage for different types of cancer diseases; however,the plausible mechanism of action of these drug molecules is not wellknown. Hence, we investigate the plausible role of antimalarial drugsin the folding and stabilization of Gq-forming DNA sequences fromthe telomere and promoter gene regions by varying the salt (KCl) concentrations,mimicking the in vitro cancerous and normal cell microenvironments.The study reveals that antimalarial drugs fold and stabilize specificallyto telomere Gq-forming sequences in the cancerous microenvironmentthan the DNA sequences located in the promoter region of the gene.Antimalarial drugs are not only able to fold Gq but also efficientlyprotect them from unfolding by their complementary strands, hencesignificantly biasing the equilibrium toward the Gq formation fromthe duplex. In contrast, in a normal cell microenvironment, K+ controls the folding of telomeres, and the role of antimalarialdrugs is not prominent. This study suggests that the action of antimalarialdrugs is sensitive to the cancer microenvironment as well as selectiveto the Gq-forming region.