Grape seeds and skin induce tumor growth inhibition via G1-phase arrest and apoptosis in mice inoculated with Ehrlich ascites carcinoma.

Abstract

Chemoprevention or intervention of cancer by means of natural dietary components has shown great promise in controlling malignancy. This study was conducted to investigate the chemopreventive effects of grape seeds (GSE) combined with grape skin (GSK) in mice that were inoculated with Ehrlich ascites carcinoma, and to elucidate the underlying mechanisms. GSE + GSK were mixed with the standard diet and supplemented to mice 14 d before Ehrlich ascites carcinoma cell inoculation and continued throughout the experiment. Tumor growth was monitored and cell cycle progression and apoptotic effect of GSE + GSK on tumor cells were evaluated. GSE + GSK intake prevented tumor development in 47% of the animals. Tumor volume and weight were markedly reduced by 93.9 % and 86.3 %, respectively, compared with tumor-bearing mice that were untreated with these agents. GSE + GSK treatment caused a marked increase in the percentage of apoptotic tumor cells as evaluated by flow cytometry and confirmed by histopathologic and electron microscopy examinations. GSE + GSK also caused significant cell cycle arrest at the G1 phase, activation of caspase-3, increase in p53 and Bax expression, and decrease in B-cell lymphoma 2 expression and B-cell lymphoma 2:Bax ratio in tumor cells. Furthermore, the induction of apoptosis and cell proliferation inhibition was indicated immunohistochemically as shown by modulating p53 and Ki67 expression. The results of this study clearly showed that the combination of GSE and GSK represents a potent chemopreventive and anticancer agent in a mice model of Ehrlich carcinoma. The mechanisms that underlie the effects of these agents include cell cycle arrest, induction of apoptosis, and inhibition of cell proliferation. These findings suggest that GSE + GSK may represent a natural, novel, adjuvant therapeutic strategy for chemoprevention of the growth of solid tumors.