Preclinical study reveals gut bacterial metabolism rapidly degrades trifluridine, indicating that the microbiome undermines oral chemotherapy efficacy in colorectal cancer.
Key Points
To identify gut bacterial species capable of metabolizing trifluridine and determine how this microbial degradation influences the drug's anticancer efficacy and downstream signaling pathways.
Conducted sequence-based homology searches across Enterobacteriaceae species to identify putative trifluridine-metabolizing enzymes.
Assessed trifluridine degradation kinetics and the inhibitory capacity of tipiracil across varying oxygen conditions using liquid chromatography–mass spectrometry (LCMS) with Escherichia coli NS-12 and Klebsiella oxytoca S-22 isolates.
Measured cancer cell cytotoxicity and evaluated the activation of p53-dependent molecular pathways following exposure to intact versus microbially degraded trifluridine.
Escherichia coli NS-12 and Klebsiella oxytoca S-22 completely degraded trifluridine within 2 hours, and the host enzyme inhibitor tipiracil only partially blocked bacterial degradation in a strain- and oxygen-dependent manner.
Pre-exposure of trifluridine to bacterial isolates abolished its cytotoxic activity against colorectal cancer cells and prevented the induction of downstream p53-dependent apoptotic pathways.