# Panobinostat Potentiates the Antitumor Efficacy of 5-Fluorouracil in Gastric Cancer by Suppressing Thymidylate Synthase Expression

## TL;DR

This study shows that panobinostat enhances the effectiveness of 5-fluorouracil in treating gastric cancer by reducing resistance linked to thymidylate synthase.

## Contribution

The novel finding is that panobinostat suppresses thymidylate synthase upregulation and oncogenic pathways, improving 5-FU efficacy in gastric cancer.

## Key findings

- Panobinostat synergizes with 5-FU to enhance cytotoxicity in gastric cancer cells.
- Panobinostat suppresses 5-FU-induced thymidylate synthase upregulation.
- Panobinostat downregulates oncogenes like c-Myc and cell cycle regulators.

## Abstract

Resistance to 5-fluorouracil (5-FU), a cornerstone chemotherapy for gastric cancer (GC), is a major clinical obstacle, often driven by the upregulation of its target enzyme, thymidylate synthase (TS). In this study, we investigated the potential of the pan-histone deacetylase inhibitor (HDACi) panobinostat to synergize with 5-FU. In GC cell lines, panobinostat treatment alone suppressed cell viability, clonogenicity, and migration, and this was associated with the induction of G1-phase cell cycle arrest and mitochondria-mediated apoptosis. Crucially, Panobinostat acted synergistically with 5-FU, leading to enhanced cytotoxicity. Mechanistically, 5-FU treatment alone induced a compensatory upregulation of TS protein, a known resistance mechanism. Panobinostat not only suppressed basal TS expression but, more importantly, abrogated this 5-FU-induced upregulation. Furthermore, panobinostat downregulated a network of oncogenes and cell cycle regulators, including c-Myc and key cyclins. These findings indicate that panobinostat can enhance 5-FU cytotoxicity by targeting TS expression and reprogramming oncogenic transcriptional networks, supporting its potential as a complementary strategy for overcoming fluoropyrimidine resistance in GC therapy.