Extended treatment with physiologic concentrations of dietary phytochemicals results in altered gene expression, reduced growth, and apoptosis of cancer cells

Abstract

Dietary phytochemicals exhibit chemopreventive potential in vivo through persistent low-dose exposures, whereas mechanistic in vitro studies with these agents generally use a high-dose single treatment. Because the latter approach is not representative of an in vivo steady state, we investigated antitumor activity of curcumin, 3,3 ¶-diindolylmethane (DIM), epigallocatechin gallate (EGCG), genistein, or indole-3-carbinol (I3C) in breast cancer MDA-MB-231 cells, exposed in long-term culture to low concentrations, achievable in vivo. Curcumin and EGCG increased cell doubling time. Curcumin, EGCG, and I3C inhibited clonogenic growth by 55% to 60% and induced 1.5-to 2-fold higher levels of the basal caspase-3/ 7 activity. No changes in expression of cell cycle -related proteins or survivin were found; however, I3C reduced epidermal growth factor receptor expression, contributing to apoptosis. Because some phytochemicals are shown to inhibit DNA and histone modification, modulation of expression by the agents in a set of genes (cadherin-11, p21Cip1, urokinase-type plasminogen activator, and interleukin-6) was compared with changes induced by inhibitors of DNA methylation or histone deacetylation. The phytochemicals modified protein and/or RNA expression of these genes, with EGCG eliciting the least and DIM the most changes in gene expression. DIM and curcumin decreased cadherin-11 and increased urokinase-type plasminogen activator levels correlated with increased cell motility. Curcumin, DIM, EGCG, and genistein reduced cell sensitivity to radiation-induced DNA damage without affecting DNA repair. This model has revealed that apoptosis and not arrest is likely to be responsible for growth inhibition. It also implicated new molecular targets and activities of the agents under conditions relevant to human exposure. [Mol Cancer Ther 2007;6(11):3071 -9]

Curcumin induces apoptosis through the mitochondria-mediated apoptotic pathway in HT-29 cells

“…Curcumin has been shown to markedly reduce the level of survivin to inhibit the growth and differentiation of KU7 bladder cancer cells (Chadalapaka et al, 2008). However, curcumin did not change the expression of survivin in DA-MB-231 cells (Moiseeva et al, 2007). In the present study, we observed that curcumin markedly down-regulated the expression of survivin in HT-29 cells, which, to our knowledge, is the first demonstration that curcumin could down-regulate the expression of the anti-apoptotic protein survivin in HT-29 cells.…”

Multi-targeted therapy of cancer by genistein

“…These results are consistent with studies reported by other investigators [43;44], clearly attesting to the fact that genistein induces apoptosis in cancer cells. This was further corroborated by recent findings of Moiseeva et.al., who reported that physiological concentrations of a dietary phytochemical including genistein results in reduced growth and induction of apoptosis of in cancer cells [45].…”

Recent advances in understanding the role of diet and obesity in the development of colorectal cancer

“…Chemopreventive attributes have been demonstrated, using animal models, for a range of foods high in particular polyphenols such as resveratrol from grapes or epigallocatechin gallate from tea (140) , and a number of mechanisms proposed including induction of apoptosis, suppression of inflammation and reduced cell proliferation (141) . In addition, epigallocatechin gallate and curcumin have been shown to modify CGI methylation in a range of cell lines including colorectal cells (142)(143)(144) . However, isoflavones not only act as oestrogen receptor ligands but have been shown by us to modify oestrogen receptor expression in the colon (137) .…”