Apigenin enhances apoptosis induction by 5-fluorouracil through regulation of thymidylate synthase in colorectal cancer cells

Changwon Yang, Jisoo Song, Sunjae Hwang, Jungil Choi, Gwonhwa Song, Whasun Lim

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number102144
JournalRedox Biology
Volume47
DOIs
Publication statusPublished - 2021 Nov

Keywords

  • Apigenin
  • Chemoresistance
  • Colon cancer
  • P53
  • Thymidylate synthase

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry

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