BIX-01294 enhances the effect of chemotherapy on colorectal cancer by inhibiting the expression of stemness genes

Biochem Biophys Res Commun. 2022 Jan 29:590:169-176. doi: 10.1016/j.bbrc.2021.12.089. Epub 2021 Dec 26.

Abstract

During the development of colorectal cancer, tumor cells will generate some cancer stem cells with self-renewal ability because they adapt to the environment. Therefore, in the treatment of colorectal cancer, it has certain potential clinical application value to effectively inhibit cancer stem cells. A small molecule EHMT-2 inhibitor, BIX-01294, was evaluated for its activity in inhibiting cancer stem cells in human colorectal cancer by in vitro and in vivo experiments. Transcriptome analysis was performed on BIX-01294 treated cells for holistic analysis to elucidate how BIX-01294 inhibits the expression of genes related to cancer stem cells. The results show that BIX-01294 significantly inhibited the proliferative phenotype of human colorectal cancer in vivo and in vitro, reduced the proportion of cancer stem cells, and inhibited some stemness-related gene. Morever, it is synergistic with 5-fluorouracil in inhibiting the proliferation of colorectal cancer. In summary, EHMT-2 is a novel target of anti-tumor drugs. The combination of BIX-01294 and 5-fluorouracil has a synergistic therapeutic effect on human colorectal cancer.

Keywords: 5-fluorouracil; BIX-01294; Cancer stem cells; Colorectal cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azepines / pharmacology
  • Azepines / therapeutic use*
  • Biomarkers, Tumor / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics*
  • Female
  • Fluorouracil / pharmacology
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Histocompatibility Antigens / genetics
  • Histocompatibility Antigens / metabolism
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Quinazolines / pharmacology
  • Quinazolines / therapeutic use*
  • Receptors, G-Protein-Coupled / metabolism

Substances

  • Azepines
  • BIX 01294
  • Biomarkers, Tumor
  • Histocompatibility Antigens
  • LGR5 protein, human
  • Quinazolines
  • Receptors, G-Protein-Coupled
  • EHMT2 protein, human
  • Histone-Lysine N-Methyltransferase
  • Fluorouracil