Polyamines in Cancer: Mechanisms, Metabolic Targets, and Therapeutic Opportunities

Polyamine metabolism is essential for cancer cell growth, with enzymes like ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC) playing key roles in polyamine (PA) biosynthesis. These polyamines (putrescine, spermidine, and spermine) regulate vital cellular processes, including DNA replication, protein synthesis, and cell cycle progression. Dysregulated polyamine metabolism is common in cancer, making ODC and AdoMetDC attractive therapeutic targets. This review highlights polyamines' role in cancer and explores combination therapies targeting polyamine metabolism and critical signaling pathways for improved clinical outcomes. A comprehensive analysis of both historical and recent literature on polyamine metabolism in cancer was performed using PubMed, which provides access to over 37 million citations from biomedical literature. Expression data for key polyamine biosynthetic enzymes, ODC and AdoMetDC, were obtained from the UALCAN portal - an interactive web resource for the analysis of cancer OMICS data. The IUPAC names of drugs and inhibitors targeting the polyamine pathway were retrieved from the PubChem database and used to generate molecular structures using the BIOVIA Draw 2025 program. Additionally, the ClinicalTrials.gov database was explored to identify ongoing and completed clinical research studies, as well as to gather detailed information on therapeutic agents targeting polyamine metabolism. Aberrant polyamine metabolism in cancer is driven by oncogenic pathways like MYC, Akt, and mTOR. MYC upregulates ODC1, promoting polyamine dysregulation. Defects in enzymes such as MTA phosphorylase (MTAP) enhance cancer cell sensitivity to inhibitors of purine/pyrimidine synthesis and the ubiquitin-proteasome pathway, suggesting alternative therapeutic strategies. Therapeutic strategies combining polyamine biosynthesis inhibition with targeting nucleotide synthesis or proteasome function have shown synergistic potential. However, the dual nature of polyamines - supporting both, tumor growth and ferroptotic cell death - poses a therapeutic challenge. Balancing these effects is key to designing effective interventions. Advancing this field requires not only selective inhibitors but also a deeper understanding of context-dependent polyamine functions in tumor biology. Developing more potent inhibitors with improved drug-like properties is crucial for advancing polyamine- targeted therapies and positioning this field at the forefront of cancer research.