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Biological and Pharmaceutical Bulletin
Vol. 38 (2015) No. 1 p. 39-47

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http://doi.org/10.1248/bpb.b14-00532

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Cardiac glycosides, which are inhibitors of Na+/K+-ATPase, are classified into cardenolides and bufadienolides. We have recently shown that two cardenolide glycosides, ouabain and odoroside A, inhibit Na+/K+-ATPase, thereby preventing nuclear factor κB-inducible protein expression by blocking Na+-dependent amino acid transport. In this study, we investigated the mechanism of action of cardenolide aglycones in tumor necrosis factor α (TNF-α)-induced gene expression. Ouabagenin, digitoxigenin, and digoxigenin were found to inhibit the TNF-α-induced cell-surface expression of intercellular adhesion molecule-1 (ICAM-1) in human lung carcinoma A549 cells. Those cardenolide aglycones did not inhibit the TNF-α-induced expression of ICAM-1 mRNA, but strongly inhibited the TNF-α-induced expression of ICAM-1 as translation product. The inhibition of the TNF-α-induced ICAM-1 expression by ouabagenin, digitoxigenin, and digoxigenin was significantly reversed by the ectopic expression of ouabain-resistant rat Na+/K+-ATPase α1 isoform. Moreover, knockdown of Na+/K+-ATPase α1 isoform augmented the inhibition of the TNF-α-induced ICAM-1 expression by ouabagenin or ouabain. These results clearly indicate that cardenolide aglycones inhibit the TNF-α-induced ICAM-1 expression at the translation step by blocking Na+/K+-ATPase.

Copyright © 2015 The Pharmaceutical Society of Japan

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