Downregulation of AP-1 gene expression is an initial event in the oridonin-mediated inhibition of colorectal cancer: studies in vitro and in vivo

J Gastroenterol Hepatol. 2011 Apr;26(4):706-15. doi: 10.1111/j.1440-1746.2010.06500.x.

Abstract

Background and aim: Oridonin is the active ingredient isolated from the Chinese herb Rabdosia rubescens. We used both in vivo and in vitro approaches to elucidate the underlying mechanism of the oridonin-mediated inhibition of colorectal cancer.

Methods: Two colorectal cell lines, Lovo and SW480, were treated with oridonin in solution. The effect of this treatment on the inhibition of the cell proliferation rate was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. The changes in gene expression that occurred in both cell lines in response to treatment with oridonin were determined via an illumine expression sensor. Additionally, a colorectal cancer colostomy implantation model was established. Animals were injected intraperitoneally with an oridonin solution.

Results: The treatment of Lovo and SW480 cells with oridonin inhibited cell proliferation in a dose-dependent manner. Furthermore, the rate of inhibition increased with prolonged treatment. The growth rate of the colorectal cancer colostomy implantation model was significantly lower than control cells when treated with oridonin (P<0.001), which meant that oridonin treatment had a significant effect on the tumor growth rate. In the tumor model, activator protein-1 (AP-1) was the only gene found to be downregulated after oridonin treatment by the gene expression sensor. After 4 weeks of treatment, AP-1, nuclear factor-κB (NF-κB) and P38 were all found to be downregulated.

Conclusions: Our study confirmed the inhibitory effects of oridonin on colorectal cancer. These results indicate that the downregulation of AP-1 might be an initial response to treatment by oridonin. This regulation could, in turn, affect the expression of the NF-κB and mitogen-activated protein kinase pathways, thereby inhibiting tumor growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Diterpenes, Kaurane / pharmacology*
  • Dose-Response Relationship, Drug
  • Down-Regulation
  • Flow Cytometry
  • Humans
  • NF-kappa B / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Transcription Factor AP-1 / genetics*
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays
  • p38 Mitogen-Activated Protein Kinases / genetics

Substances

  • Antineoplastic Agents, Phytogenic
  • Diterpenes, Kaurane
  • NF-kappa B
  • Transcription Factor AP-1
  • oridonin
  • p38 Mitogen-Activated Protein Kinases