Triptolide, histone acetyltransferase inhibitor, suppresses growth and chemosensitizes leukemic cells through inhibition of gene expression regulated by TNF-TNFR1-TRADD-TRAF2-NIK-TAK1-IKK pathway

Biochem Pharmacol. 2011 Nov 1;82(9):1134-44. doi: 10.1016/j.bcp.2011.07.062. Epub 2011 Jul 27.

Abstract

Triptolide, a diterpene triepoxide, from the Chinese herb Tripterygium wilfordii Hook.f, exerts its anti-inflammatory and immunosuppressive activities by inhibiting the transcription factor nuclear factor-κB (NF-κB) pathway, through a mechanism not yet fully understood. We found that triptolide, in nanomolar concentrations, suppressed both constitutive and inducible NF-κB activation, but did not directly inhibit binding of p65 to the DNA. The diterpene did block TNF-induced ubiquitination, phosphorylation, and degradation of IκBα, the inhibitor of NF-κB and inhibited acetylation of p65 through suppression of binding of p65 to CBP/p300. Triptolide also inhibited the IκBα kinase (IKK) that activates NF-κB and phosphorylation of p65 at serine 276, 536. Furthermore, the NF-κB reporter activity induced by TNF-TNFR1-TRADD-TRAF2-NIK-TAK1-IKKβ was abolished by the triepoxide. Triptolide also abrogated TNF-induced expression of cell survival proteins (XIAP, Bcl-x(L), Bcl-2, survivin, cIAP-1 and cIAP-2), cell proliferative proteins (cyclin D1, c-myc and cyclooxygenase-2), and metastasis proteins (ICAM-1 and MMP-9). This led to enhancement of apoptosis induced by TNF, taxol, and thalidomide by the diterpene and to suppression of tumor invasion. Overall, our results demonstrate that triptolide can block the inflammatory pathway activated by TNF-TNFR1-TRADD-TRAF2-NIK-TAK1-IKK, sensitizes cells to apoptosis, and inhibits invasion of tumor cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology
  • Cell Line
  • Cell Proliferation / drug effects
  • Diterpenes / administration & dosage
  • Diterpenes / chemistry
  • Diterpenes / pharmacology*
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Epoxy Compounds / administration & dosage
  • Epoxy Compounds / chemistry
  • Epoxy Compounds / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Histone Acetyltransferases / antagonists & inhibitors
  • Humans
  • Inflammation / metabolism
  • Leukemia / pathology
  • Molecular Structure
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Paclitaxel / administration & dosage
  • Paclitaxel / pharmacology
  • Phenanthrenes / administration & dosage
  • Phenanthrenes / chemistry
  • Phenanthrenes / pharmacology*
  • Signal Transduction / drug effects*
  • Thalidomide / administration & dosage
  • Thalidomide / pharmacology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Antineoplastic Agents
  • Diterpenes
  • Enzyme Inhibitors
  • Epoxy Compounds
  • NF-kappa B
  • Phenanthrenes
  • Tumor Necrosis Factor-alpha
  • triptolide
  • Thalidomide
  • Histone Acetyltransferases
  • Paclitaxel