Herbal diterpenoids induce growth arrest and apoptosis in colon cancer cells with increased expression of the nonsteroidal anti-inflammatory drug-activated gene

Eur J Pharmacol. 2007 Mar 15;559(1):1-13. doi: 10.1016/j.ejphar.2006.12.004. Epub 2006 Dec 23.

Abstract

Novel chemotherapeutic agents derived from active phytochemicals could be used as adjuvants and improve the anti-carcinogenicity of standard drug treatments. However, their precise mechanisms of action are sometimes unclear. In this study, the anti-carcinogenic effect of the herbal diterpenoid pseudolaric acid B (PAB) on the growth and apoptosis of colon cancer cells was investigated, and to compare that with the more toxic compound triptolide. PAB induced growth inhibition and apoptosis in HT-29 cells, which were associated with cell cycle arrest at the G(2)/M phase, modulation of cyclin expression and downregulation of the protooncogene c-myc. In addition, PAB also inhibited bcl-x(L) expression, induced cleavage of procaspase-3 and its substrate poly(ADP-ribose) polymerase (PARP), which together caused DNA fragmentation and nuclear chromatin condensation. Concomitantly, the modulation of the growth-related and apoptotic factors by PAB was accompanied by the increased protein and gene expression of the nonsteroidal anti-inflammatory drug-activated gene (NAG-1), which occurred along with cyclooxygenase-2 inhibition. The effects of PAB on PARP cleavage and NAG-1 overexpression were not reversible upon removal of the drug from the culture medium. Similar cytotoxic and pro-apoptotic effects were also attained by treating the HT-29 cells with another diterpenoid triptolide, but its actions on cell cycle progression and on the upstream transcriptional regulation of NAG-1 both took place in a less coherent manner. These findings exemplify the potential of herbal terpenoids, particularly PAB, in modulating colon cancer carcinogenesis through known molecular targets and precise mechanism of action.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic*
  • Apoptosis / drug effects*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Nucleus / drug effects
  • Cell Nucleus / ultrastructure
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / pathology*
  • Cyclooxygenase 2 / biosynthesis
  • Cytokines / genetics*
  • DNA Fragmentation / drug effects
  • Diterpenes / pharmacology*
  • Epoxy Compounds / pharmacology
  • Flow Cytometry
  • Fluorescent Dyes
  • Gene Expression Regulation, Neoplastic / drug effects
  • Growth Differentiation Factor 15
  • HT29 Cells
  • Humans
  • Immunoblotting
  • Indoles
  • PPAR gamma / biosynthesis
  • Phenanthrenes / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tetrazolium Salts
  • Thiazoles

Substances

  • Antineoplastic Agents, Phytogenic
  • Cytokines
  • Diterpenes
  • Epoxy Compounds
  • Fluorescent Dyes
  • GDF15 protein, human
  • Growth Differentiation Factor 15
  • Indoles
  • PPAR gamma
  • Phenanthrenes
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Tetrazolium Salts
  • Thiazoles
  • triptolide
  • DAPI
  • pseudolaric acid B
  • Cyclooxygenase 2
  • thiazolyl blue