title: (+)-Strebloside-Induced Cytotoxicity in Ovarian Cancer Cells Is Mediated through Cardiac Glycoside Signaling Networks.
abstract: (+)-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.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.
authors.forename: Wei-Lun
authors.identifier: 0000-0003-3703-8531
authors.initials: WL
authors.lastname: Chen
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Molecular Pharmacology and Therapeutics, Loyola University , Chicago, Illinois 60153, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Erxleben
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Johnson
authors.affiliation: Department of Molecular Pharmacology and Therapeutics, Loyola University , Chicago, Illinois 60153, United States.
authors.forename: Saverio
authors.initials: S
authors.lastname: Gentile
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, United States.
authors.forename: A Douglas
authors.identifier: 0000-0002-6647-8707
authors.initials: AD
authors.lastname: Kinghorn
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.|School of Pharmacy, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Swanson
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago , Chicago, Illinois 60612, United States.
authors.forename: Joanna E
authors.initials: JE
authors.lastname: Burdette
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077216:Carcinoma, Ovarian Epithelial; D002301:Cardiac Glycosides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D004077:Digoxin / Q000494:pharmacology; D005260:Female; D019073:HT29 Cells; D006801:Humans; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial; D010042:Ouabain / Q000494:pharmacology; D010051:Ovarian Neoplasms; D015398:Signal Transduction / Q000187:drug effects; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002301:Cardiac Glycosides; D016328:NF-kappa B; C000621345:strebloside-; D010042:Ouabain; D004077:Digoxin; D000254:Sodium-Potassium-Exchanging ATPase