Gut Microbial Metabolite 4‑Ethylphenylsulfate Is Selectively Deleterious and Anticancer to Colon Cancer Cells

Gut microbiota-derived metabolites have emerged as promising
candidates
in cancer therapeutics. Among these metabolites, 4-ethylphenyl sulfate
(4-EPS), produced through dietary metabolism, is linked to chronic
diseases but remains unexplored as a therapeutic agent for colorectal
cancer (CRC) treatment. This study investigates the selective anticancer
activity of 4-EPS using HCT-116 human colorectal adenocarcinoma cells
and CCD 841 normal colon epithelial cells. Treatment with 4-EPS significantly
reduced cell proliferation, viability, ATP levels, and colony-forming
ability while increased apoptosis rate. Morphological changes included
cell shrinkage, intracellular vesicle formation, and loss of membrane
integrity. Mechanistically, 4-EPS upregulated Bax, downregulated Bcl2,
and induced G2/M phase cell cycle arrest. In silico investigations
revealed strong interactions with HDAC isoforms, suggesting epigenetic
modulation. Markedly, 4-EPS treatment showed no deleterious effect
on CCD 841 normal colon epithelial cells, which proved its selective
anticancer role for colon cancer cells. These findings highlight 4-EPS
as a promising therapeutic agent for treating CRC.