Structural Insights into the Interactions of Digoxin and Na<sup>+</sup>/K<sup>+</sup>-ATPase and Other Targets for the Inhibition of Cancer Cell Proliferation
Digoxin is a cardiac glycoside long used to treat congestive heart failure and found recently to show antitumor potential. The hydroxy groups connected at the C-12, C-14, and C-3′a positions; the C-17 unsaturated lactone unit; the conformation of the steroid core; and the C-3 saccharide moiety have...
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| Format: | Article |
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MDPI AG
2021-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/12/3672 |
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| author | Yulin Ren Sijin Wu Joanna E. Burdette Xiaolin Cheng A. Douglas Kinghorn |
| author_facet | Yulin Ren Sijin Wu Joanna E. Burdette Xiaolin Cheng A. Douglas Kinghorn |
| author_sort | Yulin Ren |
| collection | DOAJ |
| description | Digoxin is a cardiac glycoside long used to treat congestive heart failure and found recently to show antitumor potential. The hydroxy groups connected at the C-12, C-14, and C-3′a positions; the C-17 unsaturated lactone unit; the conformation of the steroid core; and the C-3 saccharide moiety have been demonstrated as being important for digoxin’s cytotoxicity and interactions with Na<sup>+</sup>/K<sup>+</sup>-ATPase. The docking profiles for digoxin and several derivatives and Na<sup>+</sup>/K<sup>+</sup>-ATPase were investigated; an additional small Asn130 side pocket was revealed, which could be useful in the design of novel digoxin-like antitumor agents. In addition, the docking scores for digoxin and its derivatives were found to correlate with their cytotoxicity, indicating a potential use of these values in the prediction of the cancer cell cytotoxicity of other cardiac glycosides. Moreover, in these docking studies, digoxin was found to bind to FIH-1 and NF-κB but not HDAC, IAP, and PI3K, suggesting that this cardiac glycoside directly targets FIH-1, Na<sup>+</sup>/K<sup>+</sup>-ATPase, and NF-κB to mediate its antitumor potential. Differentially, digoxigenin, the aglycon of digoxin, binds to HDAC and PI3K, but not FIH-1, IAP, Na<sup>+</sup>/K<sup>+</sup>-ATPase, and NF-κB, indicating that this compound may target tumor autophagy and metabolism to mediate its antitumor propensity. |
| first_indexed | 2024-03-10T10:21:51Z |
| format | Article |
| id | doaj.art-cf2af8afb5864485b4acb150f6f0891c |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T10:21:51Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-cf2af8afb5864485b4acb150f6f0891c2023-11-22T00:20:59ZengMDPI AGMolecules1420-30492021-06-012612367210.3390/molecules26123672Structural Insights into the Interactions of Digoxin and Na<sup>+</sup>/K<sup>+</sup>-ATPase and Other Targets for the Inhibition of Cancer Cell ProliferationYulin Ren0Sijin Wu1Joanna E. Burdette2Xiaolin Cheng3A. Douglas Kinghorn4Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USADivision of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USADepartment of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USADivision of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USADivision of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USADigoxin is a cardiac glycoside long used to treat congestive heart failure and found recently to show antitumor potential. The hydroxy groups connected at the C-12, C-14, and C-3′a positions; the C-17 unsaturated lactone unit; the conformation of the steroid core; and the C-3 saccharide moiety have been demonstrated as being important for digoxin’s cytotoxicity and interactions with Na<sup>+</sup>/K<sup>+</sup>-ATPase. The docking profiles for digoxin and several derivatives and Na<sup>+</sup>/K<sup>+</sup>-ATPase were investigated; an additional small Asn130 side pocket was revealed, which could be useful in the design of novel digoxin-like antitumor agents. In addition, the docking scores for digoxin and its derivatives were found to correlate with their cytotoxicity, indicating a potential use of these values in the prediction of the cancer cell cytotoxicity of other cardiac glycosides. Moreover, in these docking studies, digoxin was found to bind to FIH-1 and NF-κB but not HDAC, IAP, and PI3K, suggesting that this cardiac glycoside directly targets FIH-1, Na<sup>+</sup>/K<sup>+</sup>-ATPase, and NF-κB to mediate its antitumor potential. Differentially, digoxigenin, the aglycon of digoxin, binds to HDAC and PI3K, but not FIH-1, IAP, Na<sup>+</sup>/K<sup>+</sup>-ATPase, and NF-κB, indicating that this compound may target tumor autophagy and metabolism to mediate its antitumor propensity.https://www.mdpi.com/1420-3049/26/12/3672digoxincytotoxicityNa<sup>+</sup>/K<sup>+</sup>-ATPasedocking profilesmolecular targets |
| spellingShingle | Yulin Ren Sijin Wu Joanna E. Burdette Xiaolin Cheng A. Douglas Kinghorn Structural Insights into the Interactions of Digoxin and Na<sup>+</sup>/K<sup>+</sup>-ATPase and Other Targets for the Inhibition of Cancer Cell Proliferation Molecules digoxin cytotoxicity Na<sup>+</sup>/K<sup>+</sup>-ATPase docking profiles molecular targets |
| title | Structural Insights into the Interactions of Digoxin and Na<sup>+</sup>/K<sup>+</sup>-ATPase and Other Targets for the Inhibition of Cancer Cell Proliferation |
| title_full | Structural Insights into the Interactions of Digoxin and Na<sup>+</sup>/K<sup>+</sup>-ATPase and Other Targets for the Inhibition of Cancer Cell Proliferation |
| title_fullStr | Structural Insights into the Interactions of Digoxin and Na<sup>+</sup>/K<sup>+</sup>-ATPase and Other Targets for the Inhibition of Cancer Cell Proliferation |
| title_full_unstemmed | Structural Insights into the Interactions of Digoxin and Na<sup>+</sup>/K<sup>+</sup>-ATPase and Other Targets for the Inhibition of Cancer Cell Proliferation |
| title_short | Structural Insights into the Interactions of Digoxin and Na<sup>+</sup>/K<sup>+</sup>-ATPase and Other Targets for the Inhibition of Cancer Cell Proliferation |
| title_sort | structural insights into the interactions of digoxin and na sup sup k sup sup atpase and other targets for the inhibition of cancer cell proliferation |
| topic | digoxin cytotoxicity Na<sup>+</sup>/K<sup>+</sup>-ATPase docking profiles molecular targets |
| url | https://www.mdpi.com/1420-3049/26/12/3672 |
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