Cyano Enone-Bearing Triterpenoid Soloxolone Methyl Inhibits Epithelial-Mesenchymal Transition of Human Lung Adenocarcinoma Cells In Vitro and Metastasis of Murine Melanoma In Vivo Научная публикация
| Журнал |
Molecules
ISSN: 1420-3049 |
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| Вых. Данные | Год: 2020, Том: 25, Номер: 24, Номер статьи : 5925, Страниц : DOI: 10.3390/molecules25245925 | ||||
| Ключевые слова | epithelial-mesenchymal transition; tumor; metastasis; triterpenoids; natural compounds; soloxolone methyl; CDDO-Me; motility; molecular docking; cytoscape | ||||
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Реферат:
Introduction of alpha-cyano alpha,beta-unsaturated carbonyl moiety into natural cyclic compounds markedly improves their bioactivities, including inhibitory potential against tumor growth and metastasis. Previously, we showed that cyano enone-bearing derivatives of 18 beta H-glycyrrhetinic (GA) and deoxycholic acids displayed marked cytotoxicity in different tumor cell lines. Moreover, GA derivative soloxolone methyl (SM) was found to induce ER stress and apoptosis in tumor cells in vitro and inhibit growth of carcinoma Krebs-2 in vivo. In this work, we studied the effects of these compounds used in non-toxic dosage on the processes associated with metastatic potential of tumor cells. Performed screening revealed SM as a hit compound, which inhibits motility of murine melanoma B16 and human lung adenocarcinoma A549 cells and significantly suppresses colony formation of A549 cells. Further study showed that SM effectively blocked transforming growth factor beta (TGF-beta)-induced epithelial-mesenchymal transition (EMT) of A549 cells: namely, inhibited TGF-beta-stimulated motility and invasion of tumor cells as well as loss of their epithelial characteristics, such as, an acquisition of spindle-like phenotype, up- and down-regulation of mesenchymal (vimentin, fibronectin) and epithelial (E-cadherin, zona occludens-1 (ZO-1)) markers, respectively. Network pharmacology analysis with subsequent verification by molecular modeling revealed that matrix metalloproteinases MMP-2/-9 and c-Jun N-terminal protein kinase 1 (JNK1) can be considered as hypothetical primary targets of SM, mediating its marked anti-EMT activity. The inhibitory effect of SM on EMT revealed in vitro was further confirmed in a metastatic model of murine B16 melanoma: SM was found to effectively block metastatic dissemination of melanoma B16 cells in vivo, increase expression of E-cadherin and suppress expression of MMP-9 in lung metastatic foci. Altogether, our data provided valuable information for a better understanding of the antitumor activity of cyano enone-bearing semisynthetic compounds and revealed SM as a promising anti-metastatic drug candidate.
Библиографическая ссылка:
Markov A.
, Odarenko K.
, Sen'kova A.
, Salomatina O.
, Salakhutdinov N.F.
, Zenkova M.A.
Cyano Enone-Bearing Triterpenoid Soloxolone Methyl Inhibits Epithelial-Mesenchymal Transition of Human Lung Adenocarcinoma Cells In Vitro and Metastasis of Murine Melanoma In Vivo
Molecules. 2020. V.25. N24. 5925 . DOI: 10.3390/molecules25245925 WOS Scopus OpenAlex
Cyano Enone-Bearing Triterpenoid Soloxolone Methyl Inhibits Epithelial-Mesenchymal Transition of Human Lung Adenocarcinoma Cells In Vitro and Metastasis of Murine Melanoma In Vivo
Molecules. 2020. V.25. N24. 5925 . DOI: 10.3390/molecules25245925 WOS Scopus OpenAlex
Даты:
| Опубликована в печати: | 14 дек. 2020 г. |
Идентификаторы БД:
| Web of science: | WOS:000603313400001 |
| Scopus: | 2-s2.0-85098607526 |
| OpenAlex: | W3111630482 |