Hydroxybenzoic Acids as Bioactive Metabolites in Cancer Prevention: Emerging Mechanisms, Structure-Activity Relationships, and Future Perspectives

Hydroxybenzoic Acids (HBAs) are naturally occurring phenolic compounds present in fruits, vegetables, and other plant-derived foods and can also be generated through metabolism or degradation of bioactive molecules, including aspirin-related compounds and dietary flavonoids. Increasing experimental evidence suggests that HBAs may contribute to some of the biological effects historically attributed to their parent compounds. Studies using HBAs have demonstrated antiproliferative activity against several cancer cell types with emerging evidence implicating Cyclin-Dependent Kinases (CDKs), CDK inhibitory proteins, and cellular transport mechanisms in these effects. Studies of salicylic acid metabolites and derivatives demonstrated that 2,3-Dihydroxybenzoic Acid (2,3-DHBA), 2,5-Dihydroxybenzoic Acid (2,5-DHBA), and related compounds can inhibit selected CDKs, while 2,4,6-Trihydroxybenzoic Acid (2,4,6-THBA), a flavonoid metabolite, exhibits particularly notable activity against multiple CDKs. Subsequent studies demonstrated that 2,4,6-THBA inhibits cancer-cell proliferation and that its cellular effects can depend upon the expression of monocarboxylate transporter SLC5A8. More recent evidence indicates that another naturally occurring metabolite, 2,3,4-Trihydroxybenzoic Acid (2,3,4-THBA), inhibits proliferation and colony formation in colon and breast cancer cells and increases expression of the CDK inhibitors p21 and p27. Collectively, these observations support a model in which HBAs may influence cancer-cell growth through multiple mechanisms determined partly by the number and positional arrangement of hydroxyl and carboxyl groups. However, mechanistic evidence remains preclinical and therefore, further biochemical, pharmacokinetic, microbiome, and in vivo investigations are therefore needed to determine whether physiologically achievable HBA concentrations can reproduce the effects observed experimentally. This review examines current evidence for the HBA metabolite hypothesis, evaluates emerging structure-activity relationships, and identifies critical questions that should be addressed to facilitate translation of these compounds from experimental models to clinical and preventive applications.