Enhancement of 5-fluorouracil efficacy in colorectal cancer cells through thymidylate synthase inhibition by sodium propionate

5-Fluorouracil (5-FU) is a cornerstone chemotherapeutic agent commonly employed in colorectal cancer (CRC) treatment. Prolonged use of 5-FU can trigger drug resistance, primarily through the upregulation of thymidylate synthase (TS). Consequently, strategies targeting TS suppression could enhance 5-FU’s therapeutic potential in resistant CRC cases. Short-chain fatty acids (SCFAs), derived from the fermentation of dietary fibers by gut microbiota, are implicated in various disease mechanisms, including cancer. Among SCFAs, sodium butyrate (NaB) is known to inhibit TS expression, reduce CRC cell viability, and promote apoptosis. However, the potential of sodium propionate (NaP), another SCFA, to exhibit similar effects remains under investigation. This study reveals that NaP, when combined with 5-FU, synergistically decreases CRC cell survival and enhances apoptosis. Furthermore, NaP counteracts the 5-FU-induced upregulation of TS, amplifying its inhibitory effects on drug-resistant CRC cells. These results suggest that NaP may serve as an effective adjunct in improving the therapeutic outcomes of 5-FU-based CRC treatments.