Pathway-specific mechanisms, therapeutic applications, and toxicodynamic profile of acriflavine in cancer: a comprehensive review.

Acriflavine (ACF), a long-established antimicrobial acridine preparation, has re-emerged as a potential candidate for drug repurposing in oncology and antiviral therapy. Its biological activity has been associated with DNA intercalation, topoisomerase inhibition, modulation of hypoxia-inducible factor (HIF) signaling, and interference with selected viral and innate immune pathways. This review critically integrates current evidence on the chemical characteristics and synthetic approaches of ACF, its pharmacological mechanisms, preclinical anticancer activity, toxicodynamic profile, and emerging drug delivery strategies. Particular emphasis is placed on HIF-associated tumor adaptation, angiogenic and metabolic signaling, DNA-processing pathways, chemotherapy sensitization, and mechanisms relevant to therapeutic resistance. Nanoparticle, liposomal, hydrogel, and localized delivery systems are also evaluated for their potential to improve tissue exposure and reduce systemic toxicity. However, the translational evidence remains limited: quantitative human pharmacokinetic data are scarce, most anticancer efficacy data derive from in vitro and animal models, and intrinsic genotoxicity and nonspecific DNA interactions remain major safety concerns. Consequently, ACF should currently be regarded as a promising preclinical candidate for repurposing rather than a clinically validated anticancer therapy. Future development will require standardized formulations, rigorous human pharmacokinetic and safety studies, improved tumor-selective delivery, and prospective clinical evaluation to establish an acceptable therapeutic index.