Triptolide suppresses growth and hormone secretion in murine pituitary corticotroph tumor cells via NF-kappaB signaling pathway

Biomed Pharmacother. 2017 Nov:95:771-779. doi: 10.1016/j.biopha.2017.08.127. Epub 2017 Sep 8.

Abstract

Triptolide is a principal diterpene triepoxide from the Chinese medical plant Tripterygium wilfordii Hook. f., whose extracts have been utilized in dealing with diverse diseases in traditional Chinese medicine for centuries. Recently, the antitumor effect of triptolide has been found in several pre-clinical neoplasm models, but its effect on pituitary corticotroph adenomas has not been investigated so far. In this study, we are aiming to figure out the antitumor effect of triptolide and address the underlying molecular mechanism in AtT20 murine corticotroph cell line. Our results demonstrated that triptolide inhibited cell viability and colony number of AtT20 cells in a dose- and time-dependent pattern. Triptolide also suppressed proopiomelanocortin (Pomc) mRNA expression and extracellular adrenocorticotropic hormone (ACTH) secretion in AtT20 cells. Flow cytometry prompted that triptolide leaded to G2/M phase arrest, apoptosis program and mitochondrial membrane depolarization in AtT20 cells. Moreover, dose-dependent activation of caspase-3 and decreased Bcl2/Bax proportion were observed after triptolide treatment. By western blot analysis we found that triptolide impeded phosphorylation of NF-κB p65 subunit and extracellular signal-regulated kinase (ERK), along with reduction of cyclin D1, without any impact on other NF-κB related protein expression like total p65, p50, IκB-α, p-IκB-α. Furthermore, the mouse xenograft model revealed the inhibition of tumor growth and hormone secretion after triptolide administration. Altogether this compound might be a potential pharmaceutical choice in managing Cushing's disease.

Keywords: ACTH; Apoptosis; Cushing’s disease; NF-κB; Triptolide.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Cycle Checkpoints / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Clone Cells
  • Corticotrophs / drug effects
  • Corticotrophs / metabolism*
  • Corticotrophs / pathology*
  • Diterpenes / pharmacology*
  • Epoxy Compounds / pharmacology
  • Female
  • Hormones / metabolism
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Mice, Nude
  • Mitochondria / metabolism
  • NF-kappa B / metabolism*
  • Phenanthrenes / pharmacology*
  • Pituitary Neoplasms / metabolism*
  • Pituitary Neoplasms / pathology*
  • Pro-Opiomelanocortin / genetics
  • Pro-Opiomelanocortin / metabolism
  • Signal Transduction* / drug effects
  • Transcription, Genetic / drug effects

Substances

  • Diterpenes
  • Epoxy Compounds
  • Hormones
  • NF-kappa B
  • Phenanthrenes
  • triptolide
  • Pro-Opiomelanocortin