Cytotoxicity of allyl isothiocyanate and its metabolites in hepatocellular carcinoma HepG2 cells

IF 1.5 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2025-01-01 DOI:10.1016/j.mrfmmm.2025.111899

Takashi Hashimoto , Shino Nakamura , Takeshi Suzuki , Yuka Hasegawa , Kazuki Kanazawa

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引用次数: 0

Abstract

Objective

To investigate the mechanisms by which allyl isothiocyanate (AITC) exerts its anticancer effects, the present study investigated the cytotoxic effects of AITC and its metabolites on hepatocellular carcinoma HepG2 cells.

Methods

The AITC metabolites, S-(N-allylthiocarbamoyl)-L-glutathione (AITC-GSH), N-acetyl-S-(N-allylthiocarbamoyl)-L-cysteine (NAC-AITC), S-(N-allylthiocarbamoyl)-L-cysteinylglycine (AITC-Cys-Gly), and S-(N-allylthiocarbamoyl)-L-cysteine (AITC-Cys) were synthesized. HepG2 cells were treated with these compounds and AITC and subjected to a cell cycle analysis, HPLC analysis for intracellular AITC metabolites, and intracellular reactive oxygen species (ROS) analysis.

Results

AITC, AITC-GSH, and NAC-AITC significantly induced cell cycle arrest in the G₂/M phase and subsequently enhanced apoptotic cell death. The AITC metabolites, AITC-Cys-Gly and AITC-Cys did not induce cell cycle arrest. A correlation was observed between the intracellular concentration of AITC-GSH and the percentage of cells under G₂/M arrest after the treatments with AITC, AITC-GSH, and NAC-AITC. AITC derived from HepG2 cells treated with AITC-GSH and NAC-AITC conjugated with endogenous GSH, resulting in an increase in ROS levels. A treatment with a ROS inhibitor canceled cell cycle arrest.

Conclusion

The conjugation of intracellular GSH with AITC decreased free reduced GSH levels and increased intracellular ROS levels in HepG2 cells, resulting in cytotoxicity, including cell cycle arrest and apoptosis.

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来源期刊

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis 生物-毒理学

CiteScore

4.90

自引率

0.00%

发文量

审稿时长

51 days

期刊介绍： Mutation Research (MR) provides a platform for publishing all aspects of DNA mutations and epimutations, from basic evolutionary aspects to translational applications in genetic and epigenetic diagnostics and therapy. Mutations are defined as all possible alterations in DNA sequence and sequence organization, from point mutations to genome structural variation, chromosomal aberrations and aneuploidy. Epimutations are defined as alterations in the epigenome, i.e., changes in DNA methylation, histone modification and small regulatory RNAs. MR publishes articles in the following areas: Of special interest are basic mechanisms through which DNA damage and mutations impact development and differentiation, stem cell biology and cell fate in general, including various forms of cell death and cellular senescence. The study of genome instability in human molecular epidemiology and in relation to complex phenotypes, such as human disease, is considered a growing area of importance. Mechanisms of (epi)mutation induction, for example, during DNA repair, replication or recombination; novel methods of (epi)mutation detection, with a focus on ultra-high-throughput sequencing. Landscape of somatic mutations and epimutations in cancer and aging. Role of de novo mutations in human disease and aging; mutations in population genomics. Interactions between mutations and epimutations. The role of epimutations in chromatin structure and function. Mitochondrial DNA mutations and their consequences in terms of human disease and aging. Novel ways to generate mutations and epimutations in cell lines and animal models.