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.
Highlights
Colon cancer is the third most diagnosed type of cancer and the third leading cause of cancer-related mortality in United States
Materials Dulbecco’s modified Eagle’s medium (DMEM) was obtained from Life Technologies (Grand Island, NY, USA); Fetal bovine serum (FBS) from PAN Biotech (GmbH, Aidenbach, Germany); Hank’s Balanced Salt Solution (HBSS), Epidermal Growth Factor (EGF) and Insulin, Transferrin, Selenium, Sodium Pyruvate solution (ITS-A) from Invitrogen; Antibodies against phosphop38, phospho-ERK1/2, phospho-jun NH -terminal kinase (JNK), beta-actin and caspases were purchased from Cell Signaling (Beverly, MA, USA) and antibodies against poly ADP ribose polymerase (PARP) was from Santa Cruz Biotechnology (Santa Cruz, CA). [6]-gingerol was purchased from Biomol (Hamburg, Germany)
In order to further understand the mechanistic details behind the inhibitory effects of [6]-gingerol on Phorbol Myristate Acetate (PMA)-activated signal pathways in SW-480, the viability and proliferation of SW-480 cells were monitored by MTT assay after treating them with various combinations of PMA, [6]-gingerol and inhibitors of mitogen-activated protein (MAP) kinases or NF-kappaB
Summary
The rhizome of ginger is an ingredient of daily diets in many countries and is an active ingredient in many traditional systems of herbal medicines, like Oriental medicine and Ayurveda, for managing many ailments including indigestion and other gastrointestinal disorders This traditional knowledge triggers a particular interest in characterizing the chemo-preventive and anticancerous nature of these phenolics against gastric cancers like colorectal cancer or pancreatic cancers. Among these phenolic compounds, [6]-gingerol (1-[49-hydroxy39-methoxyphenyl]-5-hydroxy-3-decanone) has been studied for its cytotoxic effects in various cancer cell lines, including colorectal cancer. The study performed an in vitro mechanistic evaluation on the inhibitory effects of [6]-gingerol on phorbol 12-myristate 13acetate (PMA) induced anti-apoptotic signals in SW-480 cells
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