RRC ID 62810
Author Eguchi H, Matsunaga T, Endo S, Ichihara K, Ikari A.
Title Kaempferide Enhances Chemosensitivity of Human Lung Adenocarcinoma A549 Cells Mediated by the Decrease in Phosphorylation of Akt and Claudin-2 Expression.
Journal Nutrients
Abstract Claudins (CLDNs) play crucial roles in the formation of tight junctions. We have reported that abnormal expression of CLDN2 confers chemoresistance in the spheroids of human lung adenocarcinoma A549 cells. A food composition, which can reduce CLDN2 expression, may function to prevent the malignant progression. Here, we found that ethanol extract of Brazilian green propolis (EBGP) and kaempferide, a major component of EBGP, decrease CLDN2 expression. In the two-dimensional culture model, EBGP decreased the tight junctional localization of CLDN2 without affecting that of zonula occludens-1, an adaptor protein, and enhanced paracellular permeability to doxorubicin, a cytotoxic anticancer drug. EBGP reduced hypoxic stress, and enhanced the accumulation and sensitivity of doxorubicin in the spheroid of A549 cells. Kaempferide dose-dependently decreased CLDN2 expression, although dihydrokaempferide and pinocembrin did not. The phosphorylation of Akt, a regulatory factor of CLDN2 expression, was inhibited by kaempferide but not by dihydrokaempferide. The 2,3-double bond in the C ring may be important to inhibit Akt. Kaempferide decreased the mRNA level and promoter activity of CLDN2, indicating that it inhibits the transcription of CLDN2. In accordance with EBGP, kaempferide decreased the tight junctional localization of CLDN2 and increased a paracellular permeability to doxorubicin, suggesting that it diminished the paracellular barrier to small molecules. In addition, kaempferide reduced hypoxic stress, and enhanced the accumulation and sensitivity of doxorubicin in the spheroids. In contrast, dihydrokaempferide did not improve the sensitivity to doxorubicin. Further study is needed using an animal model, but we suggest that natural foods abundantly containing kaempferide are candidates for the prevention of the chemoresistance of lung adenocarcinoma.
Volume 12(4)
Published 2020-4-23
DOI 10.3390/nu12041190
PII nu12041190
PMID 32340376
PMC PMC7230790
MeSH A549 Cells Adenocarcinoma of Lung / genetics* Adenocarcinoma of Lung / pathology* Claudin-2 / genetics Claudin-2 / metabolism* Drug Resistance, Neoplasm / drug effects Drug Resistance, Neoplasm / genetics Gene Expression / drug effects Gene Expression / genetics Gene Expression Regulation, Neoplastic / drug effects* Humans Kaempferols / pharmacology* Lung Neoplasms / genetics* Lung Neoplasms / pathology* Phosphorylation Proto-Oncogene Proteins c-akt / genetics Proto-Oncogene Proteins c-akt / metabolism*
IF 4.546
Human and Animal Cells A549(RCB0098)