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

Joshua KO*, Wan C. Leung, Wai K. Ho, Pauline Chiu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)

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 G2/M phase, modulation of cyclin expression and downregulation of the protooncogene c-myc. In addition, PAB also inhibited bcl-xL 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.

Original languageEnglish
Pages (from-to)1-13
Number of pages13
JournalEuropean Journal of Pharmacology
Volume559
Issue number1
DOIs
Publication statusPublished - 15 Mar 2007

Scopus Subject Areas

  • Pharmacology

User-Defined Keywords

  • Apoptosis
  • Colon cancer
  • Growth arrest
  • NAG-1
  • Pseudolaric acid B
  • Triptolide

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