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(+)-Strebloside-Induced Cytotoxicity in Ovarian Cancer Cells Is Mediated through Cardiac Glycoside Signaling Networks

journal contribution
posted on 06.05.2022, 15:57 authored by Wei-Lun Chen, Yulin Ren, Jinhong Ren, Christian Erxleben, Michael JohnsonMichael Johnson, Saverio GentileSaverio Gentile, A Douglas Kinghorn, Steven M Swanson, Joanna BurdetteJoanna Burdette
(+)-Strebloside, a cardiac glycoside isolated from the stem bark of Streblus asper collected in Vietnam, has shown some potential for further investigation as an antineoplastic agent. A mechanistic study using an in vitro assay and molecular docking analysis indicated that (+)-strebloside binds and inhibits Na+/K+-ATPase in a similar manner to digitoxin. Inhibition of growth of different high-grade serous ovarian cancer cells including OVCAR3, OVSAHO, Kuramochi, OVCAR4, OVCAR5, and OVCAR8 resulted from treatment with (+)-strebloside. Furthermore, this compound blocked cell cycle progression at the G2 phase and induced PARP cleavage, indicating apoptosis activation in OVCAR3 cells. (+)-Strebloside potently inhibited mutant p53 expression through the induction of ERK pathways and inhibited NF-κB activity in human ovarian cancer cells. However, in spite of its antitumor potential, the overall biological activity of (+)-strebloside must be regarded as being typical of better-known cardiac glycosides such as digoxin and ouabain. Further chemical alteration of cardiac glycosides might help to reduce negative side effects while increasing cancer cell cytotoxicity.

Funding

Discovery of Anticancer Agents of Diverse Natural Origin | Funder: NIH / NCI | Grant ID: P01 5P01CA125066-08

History

Citation

Chen, W. -L., Ren, Y., Ren, J., Erxleben, C., Johnson, M. E., Gentile, S., Kinghorn, A. D., Swanson, S. M.Burdette, J. E. (2017). (+)-Strebloside-Induced Cytotoxicity in Ovarian Cancer Cells Is Mediated through Cardiac Glycoside Signaling Networks. Journal of Natural Products, 80(3), 659-669. https://doi.org/10.1021/acs.jnatprod.6b01150

Publisher

American Chemical Society (ACS)

Language

en

issn

0163-3864