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

TL;DR

This study shows that hydroxychloroquine can inhibit cancer progression by stabilizing G-quadruplex DNA structures in the c-myc oncogene, reducing cancer cell invasion and migration.

Contribution

The study reveals a novel mechanism by which hydroxychloroquine represses c-myc transcription through G4 stabilization, offering a new strategy for cancer therapy.

Findings

Hydroxychloroquine most efficiently stabilizes G4 structures in oncogenic DNA compared to other quinoline-based drugs.

Stabilization of c-myc G4 by hydroxychloroquine suppresses its transcriptional activity and reduces breast cancer cell migration.

Hydroxychloroquine enhances the efficacy of conventional chemotherapeutics in vivo, suggesting potential as an adjunct therapy.

Abstract

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.

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