Fraxetin induces cell death in colon cancer cells via mitochondria dysfunction and enhances therapeutic effects in 5-fluorouracil resistant cells

Minkyeong Lee, Changwon Yang, Sunwoo Park, Gwonhwa Song, Whasun Lim

Research output: Contribution to journalArticlepeer-review

Abstract

Fraxetin is a natural compound extracted from Fraxinus spp. and has various functions such as antibacterial, antioxidant, neuroprotective, and antifibrotic effects. Although studies have reported its anticancer properties in lung and breast cancer, little is known about colon cancer, the most frequent type of cancer. Thus, we used two colon cancer cell lines, HT29 and HCT116 cells, to investigate whether fraxetin could inhibit the capabilities acquired during tumor development. In this study, fraxetin suppressed cell viability and induced apoptotic cell death in HT29 and HCT116 cells. Furthermore, fraxetin regulated the expression of proteins involved in apoptosis in HT29 and HCT116 cells. Additionally, fraxetin induced reactive oxygen species levels and calcium influx with loss of mitochondrial membrane potential (ΔΨm) and endoplasmic reticulum stress. Moreover, fraxetin induced G2/M arrest and modulated the intracellular signaling pathway, including AKT, ERK1/2, JNK, and P38. Nevertheless, we found no cause-effect correlation between the antiproliferative action of fraxetin and modulation of the phosphorylation state of signaling proteins. Fraxetin-induced inhibitory effect on colon cancer cell viability was synergistic with 5-fluorouracil (5-FU) or irinotecan even in 5-FU resistant-HCT116 cells. Collectively, our results suggest that fraxetin can be effectively used as a therapeutic agent for targeting colon cancer, although it is necessary to further elucidate the relationship between the hallmark capabilities that fraxetin inhibits and the intracellular regulatory mechanism.

Original languageEnglish
JournalJournal of cellular biochemistry
DOIs
Publication statusAccepted/In press - 2021

Keywords

  • apoptosis
  • chemoresistance
  • colon cancer
  • fraxetin
  • mitochondria

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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