[6]-Gingerol induces caspase-dependent apoptosis and prevents PMA-induced proliferation in colon cancer cells by inhibiting MAPK/AP-1 signaling

PLoS One. 2014 Aug 26;9(8):e104401. doi: 10.1371/journal.pone.0104401. eCollection 2014.

Abstract

We report mechanism-based evidence for the anticancer and chemopreventive efficacy of [6]-gingerol, the major active principle of the medicinal plant, Ginger (Zingiber officinale), in colon cancer cells. The compound was evaluated in two human colon cancer cell lines for its cytotoxic effect and the most sensitive cell line, SW-480, was selected for the mechanistic evaluation of its anticancer and chemopreventive efficacy. The non-toxic nature of [6]-gingerol was confirmed by viability assays on rapidly dividing normal mouse colon cells. [6]-gingerol inhibited cell proliferation and induced apoptosis as evidenced by externalization of phosphatidyl serine in SW-480, while the normal colon cells were unaffected. Sensitivity to [6]-gingerol in SW-480 cells was associated with activation of caspases 8, 9, 3 &7 and cleavage of PARP, which attests induction of apoptotic cell death. Mechanistically, [6]-gingerol down-regulated Phorbol Myristate Acetate (PMA) induced phosphorylation of ERK1/2 and JNK MAP kinases and activation of AP-1 transcription factor, but had only little effects on phosphorylation of p38 MAP kinase and activation of NF-kappa B. Additionally, it complemented the inhibitors of either ERK1/2 or JNK MAP kinase in bringing down the PMA-induced cell proliferation in SW-480 cells. We report the inhibition of ERK1/2/JNK/AP-1 pathway as a possible mechanism behind the anticancer as well as chemopreventive efficacy of [6]-gingerol against colon cancer.

MeSH terms

  • Anticarcinogenic Agents / chemistry
  • Anticarcinogenic Agents / pharmacology*
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects
  • Carcinogens / toxicity
  • Caspases / metabolism
  • Catechols / chemistry
  • Catechols / pharmacology*
  • Cell Line, Tumor
  • Colon / drug effects
  • Colon / metabolism
  • Colonic Neoplasms / chemically induced
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / prevention & control
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Fatty Alcohols / chemistry
  • Fatty Alcohols / pharmacology*
  • Ginger / chemistry
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Signal Transduction / drug effects
  • Tetradecanoylphorbol Acetate / toxicity
  • Transcription Factor AP-1 / metabolism*

Substances

  • Anticarcinogenic Agents
  • Antineoplastic Agents, Phytogenic
  • Carcinogens
  • Catechols
  • Fatty Alcohols
  • Transcription Factor AP-1
  • gingerol
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Caspases
  • Tetradecanoylphorbol Acetate

Grant support

The authors have no support or funding to report.