Subtype-specific activation of estrogen receptors by a special extract of Rheum rhaponticum (ERr 731), its aglycones and structurally related compounds in U2OS human osteosarcoma cells

Phytomedicine. 2007 Nov;14(11):716-26. doi: 10.1016/j.phymed.2007.09.001.

Abstract

The special extract ERr 731 from the roots of Rheum rhaponticum is the major constituent of Phytoestrol N which is used for the alleviation of menopausal symptoms. Recently, we demonstrated that ERr 731 and its aglycones trans-rhapontigenin and desoxyrhapontigenin as single test substances do not activate the estrogen receptors-alpha (ERalpha) in human endometrial adenoarcinoma cells. However, these substances together with the structurally related hydroxystilbenes cis-rhapontigenin, resveratrol and piceatannol activated the ERbeta-dependent reporter gene activity. To investigate if these substance are tissue selective ER activators, ERr 731 and the single test substances were examined in bone-derived U2OS cells stably expressing ERalpha or transiently expressing ERbeta. In the ERalpha expressing U2OS cells, a weak, but statistically significant ERalpha-coupled luciferase activity was detected with ERr 731 and desoxyrhapontigenin which was 10-times lower than with 10(8) M 17 beta-estradiol. In the ERbeta test system, all test substances significantly induced the luciferase activity in a magnitude comparable to 17beta-estradiol. All effects were abolished with the pure ER antagonist ICI 182 780, indicating an ER-specific effect. Intracellular actions were also examined with the glycosylated ERr 731 constituents rhaponticin and desoxyrhaponticin. Treatment of U2OS cells with defined mixtures of both glycosides resulted in a reporter gene activity comparable to that of ERr 731, thereby providing evidence for the existence of cellular uptake mechanisms for glycosylated hydroxystilbenes. This report confirms the strong ERbeta-dependent activity of ERr 731 and provides evidence for a tissue selective ER agonistic activity by ERr 731 and its aglycones, as demonstrated by the activation of ERalpha in bone cells but not in endometrial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Antineoplastic Agents, Phytogenic / therapeutic use
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / metabolism
  • Dose-Response Relationship, Drug
  • Estrogen Antagonists / administration & dosage
  • Estrogen Antagonists / chemistry
  • Estrogen Antagonists / pharmacology*
  • Estrogen Antagonists / therapeutic use
  • Estrogen Receptor alpha / metabolism
  • Estrogen Receptor beta / metabolism
  • Humans
  • Osteosarcoma / drug therapy
  • Osteosarcoma / pathology
  • Phytotherapy*
  • Plant Extracts / administration & dosage
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacokinetics
  • Plant Extracts / pharmacology*
  • Plant Extracts / therapeutic use
  • Receptors, Estrogen / metabolism*
  • Rheum*

Substances

  • Antineoplastic Agents, Phytogenic
  • ERr 731
  • Estrogen Antagonists
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Plant Extracts
  • Receptors, Estrogen