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Article

Kaempferide Enhances Chemosensitivity of Human Lung Adenocarcinoma A549 Cells Mediated by the Decrease in Phosphorylation of Akt and Claudin-2 Expression

1
Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan
2
Education Center of Green Pharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 502-8585, Japan
3
Nagaragawa Research Center, API Co., Ltd., Gifu 502-0071, Japan
*
Author to whom correspondence should be addressed.
Received: 21 March 2020 / Revised: 18 April 2020 / Accepted: 21 April 2020 / Published: 23 April 2020
(This article belongs to the Section Nutrition and Metabolism)
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. View Full-Text
Keywords: claudin; lung adenocarcinoma; chemoresistance; flavonoid claudin; lung adenocarcinoma; chemoresistance; flavonoid
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MDPI and ACS Style

Eguchi, H.; Matsunaga, T.; Endo, S.; Ichihara, K.; Ikari, A. Kaempferide Enhances Chemosensitivity of Human Lung Adenocarcinoma A549 Cells Mediated by the Decrease in Phosphorylation of Akt and Claudin-2 Expression. Nutrients 2020, 12, 1190. https://0-doi-org.brum.beds.ac.uk/10.3390/nu12041190

AMA Style

Eguchi H, Matsunaga T, Endo S, Ichihara K, Ikari A. Kaempferide Enhances Chemosensitivity of Human Lung Adenocarcinoma A549 Cells Mediated by the Decrease in Phosphorylation of Akt and Claudin-2 Expression. Nutrients. 2020; 12(4):1190. https://0-doi-org.brum.beds.ac.uk/10.3390/nu12041190

Chicago/Turabian Style

Eguchi, Hiroaki, Toshiyuki Matsunaga, Satoshi Endo, Kenji Ichihara, and Akira Ikari. 2020. "Kaempferide Enhances Chemosensitivity of Human Lung Adenocarcinoma A549 Cells Mediated by the Decrease in Phosphorylation of Akt and Claudin-2 Expression" Nutrients 12, no. 4: 1190. https://0-doi-org.brum.beds.ac.uk/10.3390/nu12041190

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