Objective: The ginger components -gingerol, and -paradol have been shown to interfere with carcinogenic processes in several cell types. Previously described mechanisms of action include inhibition of EGF-induced cell transformation and AP-1 activation and induction of apoptosis. Ginger exerts inhibitory effects on prostaglandin and leukotriene biosynthesis, indicating that the antineoplastic effects of gingerol are also associated with anti-oxidant and/or anti-inflammatory function. A pro-inflammatory state may contribute towards ovarian carcinogenesis. In the present study, we explored the response of ovarian cancer cells to ginger in vitro. Methods: A panel of ovarian cancer cell lines was treated with ginger solubilized in DMSO. Pharmaceutical grade whole ginger extract standardized to 5% -gingerol, was used. Cell viability was determined with sulforhodamine assays. Ginger effect on VEGF, IL-8 and PGE-2 expression was determined via ELISA assay. Apoptosis was determined by sub G0 analysis by flow cytometry, and by immunoblotting for expression of caspase-9. Morphologic analysis was performed using light and electron microscopy. Autophagy was determined by transiently transfecting cells with GFP labeled LC3 and quantifying activated LC3 using immunofluroescence microscopy. Results: Ginger induced cell death as determined with sulforhodamine assay in all ovarian cancer cell lines tested. The extent of apoptotic cell death as indicated by cleavage of caspase-9 by immunoblotting and Sub Go analysis by flow cytometry was less than expected, suggesting that non-apoptotic cell death was also occurring. Morphologic analysis indicated the presence of autophagy; this was confirmed by immunofluorescence microscopic examination of activated LC3-GFP in ginger treated cells. Ginger treatement also resulted in decreased production of VEGF, IL-8 and PGE-2 in ovarian cancer cells. Conclusion: Ginger induces cell death in ovarian cancer cells through apoptosis as well as the induction of autophagy. The majority of conventional chemotherapeutic agents induce apoptotic cell death. Because ginger can circumvent chemoresistance due to alterations in apoptotic signaling, it has the potential to be effective against chemoresistant disease. Our preliminary results indicate that ginger is a nutraceutical that may have significant therapeutic benefit for ovarian cancer patients.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]