β-Ionone enhances the inhibitory effects of 5-fluorouracil on the proliferation of gastric adenocarcinoma cells by the GSK-3β signaling pathway

PLoS One. 2024 Sep 6;19(9):e0309014. doi: 10.1371/journal.pone.0309014. eCollection 2024.

Abstract

5-Fluorouracil (5-FU) is widely used in the treatment of gastric cancer, and the emergence of drug resistance and toxic effects has limited its application. Therefore, there is an urgent need for safe and effective novel drugs or new therapies. β-Ionone (BI) is found in vegetables and fruits and possesses an inhibitory proliferation of tumor cells in vitro and in vivo. In this study, we investigated whether BI could enhance the inhibitory effects of 5-FU on the proliferation of gastric adenocarcinoma cells and the growth of gastric cancer cell xenografts in a mouse model. The effects of BI and 5-FU alone or their combination on the cell viability, apoptosis, and mitochondrial membrane potential, the cell cycle, and its related proteins-Cyclin D1, and CDK4 as well as PCNA and GSK-3β were evaluated in SGC-7901 cells and MKN45 cells by MTT, MB, flow cytometry and Western blot. In addition, the effects of BI and 5-FU alone or their combination on the growth of SGC-7901 cell xenografts in nude mice were investigated. The results showed that BI significantly enhanced the sensitivity of gastric adenocarcinoma cells to 5-FU in vitro and in vivo, i.e. proliferation inhibited, apoptosis induced and GSK-3β protein activated. Therefore, our results suggest that BI increases the antitumor effect of 5-FU on gastric adenocarcinoma cells, at least partly from an activated GSK-3β signaling pathway.

MeSH terms

  • Adenocarcinoma* / drug therapy
  • Adenocarcinoma* / metabolism
  • Adenocarcinoma* / pathology
  • Animals
  • Apoptosis* / drug effects
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Cell Survival / drug effects
  • Cyclin-Dependent Kinase 4 / metabolism
  • Drug Synergism
  • Fluorouracil* / pharmacology
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta* / metabolism
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude*
  • Norisoprenoids* / pharmacology
  • Signal Transduction* / drug effects
  • Stomach Neoplasms* / drug therapy
  • Stomach Neoplasms* / metabolism
  • Stomach Neoplasms* / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Fluorouracil
  • Glycogen Synthase Kinase 3 beta
  • Norisoprenoids
  • beta-ionone
  • GSK3B protein, human
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3
  • Cyclin-Dependent Kinase 4

Grants and funding

This project was supported by the National Natural Science Foundation of China (No. 82172580) and partially supported by Xi'an No. 9 Hospital Fund (No. 2022yb11). Dr. Jia-Ren Liu had the conceptualization, methodology, supervision, writing - review & editing, resources, funding acquisition, and project administration.