Although effective drugs have been developed, including 5-fluorouracil (5-FU), advanced colorectal cancer (CRC) shows low therapeutic sensitivity resulting from the development of 5-FU resistance. Thymidylate synthase (TS) is a target protein of 5-FU, and elevated TS lowers the 5-FU sensitivity of CRC cells. Here, we tested the efficacy of several candidate phytochemicals against human CRC-derived HCT116 cells expressing wild-type tumor suppressor protein P53 and HT29 cells expressing mutant P53. Among them, we found that apigenin enhanced the inhibitory effect of 5-FU on cell viability. In addition, apigenin inhibited the upregulation of TS induced by 5-FU. Apigenin also potentiated 5-FU-induced apoptosis of HCT116 cells and enhanced cell cycle disruption. Furthermore, apigenin increased reactive oxygen species production, intracellular and intramitochondrial Ca²⁺ concentrations, and mitochondrial membrane potential upon cotreatment with 5-FU. Knockdown of forkhead box protein M, a transcription factor modulating 5-FU sensitivity, enhanced the potentiation of apoptosis by apigenin in HCT116 cells. Moreover, apigenin suppressed TS expression and inhibited the viability of 5-FU-resistant HCT116 cells. Therefore, apigenin may improve the therapeutic efficacy of 5-FU against CRC by suppressing TS, but apoptosis induction is mainly dependent on functional P53.

尽管已经开发出包括 5-氟尿嘧啶 (5-FU) 在内的有效药物，但由于 5-FU 耐药性的发展，晚期结直肠癌 (CRC) 显示出较低的治疗敏感性。胸苷酸合酶 (TS) 是 5-FU 的靶蛋白，TS 升高会降低 CRC 细胞对 5-FU 的敏感性。在这里，我们测试了几种候选植物化学物质对表达野生型肿瘤抑制蛋白 P53 的人类 CRC 衍生的 HCT116 细胞和表达突变 P53 的 HT29 细胞的功效。其中，我们发现芹菜素增强了5-FU对细胞活力的抑制作用。此外，芹菜素抑制 5-FU 诱导的 TS 上调。芹菜素还增强了 5-FU 诱导的 HCT116 细胞凋亡并增强了细胞周期中断。此外，芹菜素增加了活性氧的产生，与 5-FU 共同处理后的^{2+浓度和线粒体膜电位。}敲除叉头盒蛋白 M（一种调节 5-FU 敏感性的转录因子）可增强 HCT116 细胞中芹菜素对细胞凋亡的增强作用。此外，芹菜素抑制 TS 表达并抑制 5-FU 抗性 HCT116 细胞的活力。因此，芹菜素可能通过抑制TS提高5-FU对CRC的治疗效果，但细胞凋亡诱导主要依赖于功能性P53。