Regulation of Chloride Channels by Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-Induced α-Defensin 5

Biol Pharm Bull. 2024;47(1):159-165. doi: 10.1248/bpb.b23-00672.

Abstract

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used to treat non-small cell lung cancer with EGFR mutations. However, first-generation erlotinib and second-generation afatinib often cause diarrhea, which may develop because of the association between EGFR-TKIs and the chloride channel or abnormalities in the intestinal microbiota due to disruption of the intestinal immune system. As reports on the effects of EGFR-TKIs on intestinal immunity are lacking, we aimed to determine whether the intestinal immune system is involved in the molecular effects of EGFR-TKIs on chloride channels using Caco-2 cells. Initially, we evaluated the association of chloride channels with α-defensin 5 (DEFA5), a marker of intestinal immunity. Erlotinib and afatinib significantly increased the extracellularly secreted DEFA5 level and autophagy-related 16-like 1 and X-box binding protein 1 transcript levels, indicative of enhanced granule exocytosis. Conversely, intracellular DEFA5 and Toll-like receptor 4 protein expression and tumor necrosis factor-α transcript levels decreased significantly, suggesting that Toll-like receptor 4 suppression repressed DEFA5 production. Furthermore, among the chloride channels, DEFA5 was found to significantly increase the transcript levels of cystic fibrosis transmembrane conductance regulators. These results indicate that DEFA5 plays a significant role in the mechanism of chloride channel-mediated diarrhea induced by EGFR-TKIs. Therefore, we successfully elucidated the potential host action of DEFA5 in cancer therapy for the first time.

Keywords: afatinib; cystic fibrosis transmembrane conductance regulator; diarrhea; erlotinib; toll-like receptor-4; transmembrane member 16a.

MeSH terms

  • Afatinib / adverse effects
  • Caco-2 Cells
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Chloride Channels / genetics
  • Chlorides / metabolism
  • Diarrhea / chemically induced
  • ErbB Receptors / metabolism
  • Erlotinib Hydrochloride / adverse effects
  • Humans
  • Lung Neoplasms* / metabolism
  • Mutation
  • Protein Kinase Inhibitors / adverse effects
  • Toll-Like Receptor 4 / metabolism
  • Tyrosine Kinase Inhibitors
  • alpha-Defensins* / metabolism

Substances

  • Afatinib
  • Erlotinib Hydrochloride
  • Toll-Like Receptor 4
  • Tyrosine Kinase Inhibitors
  • alpha-Defensins
  • Protein Kinase Inhibitors
  • Chlorides
  • ErbB Receptors
  • Chloride Channels