Differential Cytotoxicity of Hydroxycinnamic Acids in Cancer Cells: Structure–Activity Insights From a Broad Panel of Cell Lines

ABSTRACT Phenolic acids, abundant in plant‐based foods, are increasingly investigated for their anticancer potential. This study systematically evaluated the cytotoxic effects of three hydroxycinnamic acids—trans‐cinnamic acid (tCA), p‐coumaric acid (pCA), and ferulic acid (FA)—across 10 cancer cell lines (A‐673, HeLa, PC‐3, SW48, HT‐29, Caco‐2, HUH‐7, MG‐63, 2A3, CARM‐L12‐TG3) and one non‐cancerous cell line (Phoenix) after 48 and 72 h of treatment. IC 50 values were determined via MTT assay. At 48 h, tCA showed the most significant reduction in metabolic activity in Caco‐2 and HUH‐7 cells, while HT‐29 was the most resistant. pCA showed selective potency in A‐673 and PC‐3 cells, whereas FA demonstrated broad cytotoxic activity, with pronounced effects in SW48 and HeLa cells. Cytotoxicity increased in a time‐dependent manner at 72 h. The non‐cancerous Phoenix cells were generally less sensitive, supporting the selective inhibitory effect of these compounds toward malignant cells. Statistical analyses revealed highly significant effects of treatment and time factors, with significant treatment and time interactions in A‐673, HeLa, and PC‐3 cells. These findings indicate that pCA is the most selective compound, FA exerts the broadest cytotoxicity, and tCA shows a balanced but time‐dependent effect. Collectively, this study highlights hydroxycinnamic acids as promising scaffolds for developing selective anticancer agents.