3',4'-dimethoxyflavone as an aryl hydrocarbon receptor antagonist in human breast cancer cells

Toxicol Sci. 2000 Dec;58(2):235-42. doi: 10.1093/toxsci/58.2.235.

Abstract

Treatment of MCF-7 and T47D human breast cancer cells with 3', 4'-dimethoxyflavone (3',4'-DMF) alone did not induce CYP1A1-dependent ethoxyresorufin O:-deethylase (EROD) activity or reporter gene activity in cells transfected with an aryl hydrocarbon (Ah)-responsive construct (pRNH11c). In contrast, 1 nM 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) induced up to a 50- to 80-fold increase in EROD and reporter gene activity in MCF-7 and T47D cells. In cells cotreated with 1 nM TCDD plus 0.1-10 microM 3',4'-DMF, there was a concentration-dependent decrease in the TCDD-induced responses, with 100% inhibition observed at the 10 microM concentration. Gel mobility shift assays using rat liver cytosol and breast cancer cell nuclear extracts showed that 3',4'-DMF alone did not transform the AhR to its nuclear binding form, but inhibited TCDD-induced AhR transformation in rat liver cytosol and blocked TCDD-induced formation of the nuclear AhR complex in MCF-7 and T47D cells. TCDD also inhibited estrogen-induced transactivation in MCF-7 cells, and this response was also blocked by 3',4'-DMF, confirming the AhR antagonist activity of this compound in breast cancer cells.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cytochrome P-450 CYP1A1 / biosynthesis
  • Dose-Response Relationship, Drug
  • Enzyme Induction / drug effects
  • Female
  • Humans
  • Male
  • Polychlorinated Dibenzodioxins / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Aryl Hydrocarbon / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Transcriptional Activation / drug effects

Substances

  • Polychlorinated Dibenzodioxins
  • Receptors, Aryl Hydrocarbon
  • Cytochrome P-450 CYP1A1