Abstract
CONTEXT: Cancer and antibiotic resistance are critical global health challenges. Phenothiazines, initially developed as antipsychotics, have demonstrated diverse biological activities, including antitumor, antibacterial, and antioxidant effects. Advances in phenothiazine synthesis have produced derivatives with broader therapeutic potential by modulating receptors, ion channels, and inducing lysosomal cell death. This review explores the therapeutic potential of phenothiazines in oncology and infectious disease management, focusing on their mechanisms of action and future clinical applications. EVIDENCE ACQUISITION: This narrative review synthesizes insights from relevant preclinical studies on phenothiazines' applications in oncology and infectious diseases. Mechanistic pathways and experimental outcomes were analyzed to highlight therapeutic potentials and limitations. RESULTS: Phenothiazines demonstrate significant potential in oncology by inhibiting tumor growth via apoptosis induction, pathway modulation (e.g., PDK1/Akt, MAPK/ERK1/2, and Akt/mTOR), angiogenesis suppression through vascular endothelial growth factor (VEGF) production inhibition, and enhancing the effectiveness of monoclonal antibody therapies. They disrupt key cancer-promoting pathways and induce lysosomal cell death. Beyond oncology, phenothiazines exhibit antibacterial activity, targeting efflux pumps (Eps) and restoring antibiotic susceptibility in multidrug-resistant (MDR) pathogens. These multifaceted actions position phenothiazines as promising agents for combination therapies in cancer treatment and antibiotic-resistant infections. CONCLUSIONS: Phenothiazines hold promise as adjuvants in cancer and antibiotic resistance management. Further research should focus on optimizing their pharmacological profiles, elucidating molecular mechanisms, and validating their efficacy through clinical trials.