G-Quadruplex–specific action of chloroquine-based immunomodulator drugs to inhibit the cancer progression

Immunomodulatory drugs, particularly hydroxychloroquine (HCQ) and chloroquine are in the preclinical investigation for cancer therapy, along with their extensive application in autoimmune and parasitic diseases. A hallmark of cancer cells is the elevated expression of oncogenes that drive tumor progression, often regulated by G-quadruplex (G4) DNA structures located within their upstream promoter regions. This study elucidates that HCQ stabilizes the cellular G4 landscape most efficiently compared to other quinoline-based immunomodulatory drugs within oncogenic DNA, particularly the c-myc oncogene, a pivotal regulator of cancer progression. The drug-induced stabilization of c-myc G4 correlates with significant suppression of its transcriptional activity, culminating in a reduction of invasion and migration of triple-negative breast cancer cells. Mechanistically, the strong electrostatic interaction between the G4 phosphate backbone and the drug's charged side chain, anchors its quinoline group to enhance stacking with loop and quartet regions, stabilizing the G4. The in vivo investigation unveils the HCQ's capacity to potentiate the efficacy of conventional chemotherapeutic agents, representing it as a plausible candidate for adjunctive therapy. This study depicts an unconventional anticancer mechanism of immunomodulator drugs, wherein it exerts preferential transcriptional repression of the c-myc oncogene through G4-dependent stabilization, unveiling a novel strategy in oncological intervention.