Synergistic antitumor effects of 5-fluorouracil and vorinostat in preclinical models of pheochromocytomas and paragangliomas.

Abstract

Purpose: Therapeutic options for metastatic pheochromocytomas and paragangliomas (PPGLs) are largely limited, highlighting the need for novel strategies. This study aimed to investigate the efficacy and safety of 5-fluorouracil (5-FU) and vorinostat (SAHA), alone or in combination in preclinical PPGL models.

Methods: The growth inhibitory effects of 5-FU and SAHA were investigated in PC-12 cells and human PPGL primary cultures (n = 4) using CCK-8 assays. Drug interactions were evaluated utilizing the Chou-Talalay method. Specific mechanisms were explored via flow cytometry, wound healing, and transwell assays. In vivo efficacy and safety were assessed using mouse subcutaneous xenograft models.

Results: Both monotherapies inhibited PC-12 growth in a dose- and time-dependent manner (5-FU: 0-160 μM and SAHA: 0-80 μM). The combination therapy (20 μM 5-FU + 10 μM SAHA) exhibited a robust synergistic effect with the combination index < 1, achieving 43% growth inhibition in PC-12 cells and nearly 70% in primary cultures, significantly outperforming monotherapies. This combination significantly exacerbated G0/G1 cell cycle arrest and suppressed PC-12 cell migration and invasion. In vivo, the combined treatment reduced final tumor volumes by approximately 50% and significantly decreased the Ki-67 index. Despite mild body weight loss on days 15 and 21, no evident histopathological organ damage was observed.

Conclusions: This study provides the first preclinical evidence that combining SAHA with 5-FU exerts a robust synergistic antitumor effect in PPGLs with no evident histopathological organ damage, laying a strong foundation for developing novel combination therapy for metastatic PPGLs.