digitoxin and gitoxigenin

Up-regulation of placental soluble fms-like tyrosine kinase 1 (sFlt1) contributes to the pathogenesis of preeclampsia. To evaluate novel upstream pathways that regulate placental sFlt1 production, we screened a library of natural compounds (n=502) in human placental cell lines. Here, we report 3 compounds in the cardiac glycoside family, ouabain, gitoxigenin, and digitoxin, that inhibit placental sFlt1 production at nanomolar concentrations in vitro. We further characterized ouabain and demonstrated that it inhibits sFlt1 mRNA and protein expression in human placental cytotrophoblasts and explant cultures in a dose- and time-dependent manner. Ouabain down-regulated sFlt1 production by inhibiting hypoxia-inducible factor 1 (HIF-1α) protein expression in the placenta. Furthermore, we found that phosphorylation of heat-shock protein 27 (HSP27) was necessary for ouabain to inhibit HIF-1α translation. In a rat model of pregnancy-induced hypertension, ouabain reduced mean arterial pressure and enhanced placental HSP27 phosphorylation without any adverse effects on pups. Further studies are needed to explore the usefulness of targeting HIF-1α/HSP27 pathway in preeclampsia.

Topics: Animals; Blood Pressure; Cardenolides; Cardiotonic Agents; Cells, Cultured; Digitoxin; Dose-Response Relationship, Drug; Female; HSP27 Heat-Shock Proteins; Humans; Hypertension, Pregnancy-Induced; Hypoxia-Inducible Factor 1, alpha Subunit; Ouabain; Phosphorylation; Placenta; Pregnancy; Rats; Rats, Sprague-Dawley; RNA, Messenger; Vascular Endothelial Growth Factor Receptor-1

Recent research has shown the anticancer effects of digitalis compounds suggesting their possible use in medical oncology. Four extracts obtained from the leaves of Digitalis purpurea subsp. heywoodii have been assessed for cytotoxic activity against three human cancer cell lines, using the SRB assay. All of them showed high cytotoxicity, producing IC50 values in the 0.78 - 15 microg/mL range with the methanolic extract being the most active, in non toxic concentrations. Steroid glycosides (gitoxigenin derivatives) were detected in this methanolic extract. Gitoxigenin and gitoxin were evaluated in the SRB assay using the three human cancer cell lines, showing IC50 values in the 0.13 - 2.8 microM range, with the renal adenocarcinoma cancer cell line (TK-10) being the most sensitive one. Morphological apoptosis evaluation of the methanolic extract and both compounds on the TK-10 cell line showed that their cytotoxicity was mediated by an apoptotic effect. Finally, possible mechanisms involved in apoptosis induction by digitalis compounds are discussed.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Cardenolides; Cell Line, Tumor; Digitalis; Digoxin; Etoposide; Humans; Inhibitory Concentration 50; Kidney Neoplasms; Phytotherapy; Plant Extracts; Plant Leaves

Topics: Cardenolides; Digitalis; Digitalis Glycosides; Isomerism; Oxidation-Reduction; Plant Extracts

Topics: Cardenolides; Digitalis; Digitalis Glycosides; Digitoxigenin; Glycosides; Plant Extracts; Plant Leaves

Topics: Cardenolides; Colorimetry; Digitalis; Digitoxigenin; Plant Extracts; Regression Analysis

Topics: Cardenolides; Digitalis; Digitalis Glycosides; Humans; Plant Extracts

Topics: Cardenolides; Digitalis; Digitalis Glycosides; Fluorometry; Plant Extracts

Topics: Cardenolides; Chromatography, Paper; Digitalis; Digitalis Glycosides; Digoxin