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

J Nat Prod. 2017 Mar 24;80(3):659-669. doi: 10.1021/acs.jnatprod.6b01150. Epub 2017 Feb 24.

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.

MeSH terms

  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / isolation & purification*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects
  • Carcinoma, Ovarian Epithelial
  • Cardiac Glycosides / chemistry
  • Cardiac Glycosides / isolation & purification*
  • Cardiac Glycosides / pharmacology*
  • Digoxin / pharmacology
  • Female
  • HT29 Cells
  • Humans
  • Molecular Structure
  • NF-kappa B / metabolism
  • Neoplasms, Glandular and Epithelial
  • Ouabain / pharmacology
  • Ovarian Neoplasms
  • Signal Transduction / drug effects
  • Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors*
  • Stereoisomerism

Substances

  • Antineoplastic Agents, Phytogenic
  • Cardiac Glycosides
  • NF-kappa B
  • strebloside-
  • Ouabain
  • Digoxin
  • Sodium-Potassium-Exchanging ATPase