Indole-3-carbinol-induced death in cancer cells involves EGFR downregulation and is exacerbated in a 3D environment

Moiseeva, Elena P.; Fox, Louise H.; Howells, Lynne; Temple, Louis A.F.; Manson, Margaret M.

doi:10.1007/s10495-006-5877-5

Cited by 20 publications

(19 citation statements)

References 40 publications

(30 reference statements)

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“…It was encouraging to note that EGFR was downregulated by I3C in the present study as observed in response to single high doses (8,9). I3C-induced reduction in vimentin was not related to decreased EGFR signaling (Fig.…”

Section: Physiological Activities Of Dietary Agentssupporting

confidence: 69%

“…Our previous studies showed that treatment of MDA-MB-231 cells with 250 Amol/L I3C decreased protein levels of EGFR, cyclin D1, and cyclin-dependent kinase 6, whereas p21Cip1, p27Kip1, and cyclin E were increased (8). We also showed that I3C-induced apoptosis is related to down-regulation of EGFR in these cells (8,9). The latter is consistent with the data obtained in this model because reduced EGFR signaling in combination with diluted autocrine transforming growth factor-a is bound to increase apoptosis and reduce growth in clonogenic assay.…”

Section: Physiological Activities Of Dietary Agentsmentioning

confidence: 75%

“…Background apoptotic activity of caspase-3/7 was measured using Caspase-Glo 3/7 kit (Promega) as described previously (9).…”

Section: Cell Culturementioning

confidence: 99%

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

Moiseeva

Almeida

Jones

et al. 2007

Molecular Cancer Therapeutics

109

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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]

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Section: Physiological Activities Of Dietary Agentssupporting

confidence: 69%

Section: Physiological Activities Of Dietary Agentsmentioning

confidence: 75%

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

Moiseeva

Almeida

Jones

et al. 2007

Molecular Cancer Therapeutics

109

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“…Other studies indicated that I3C down regulated epidermal growth factor receptor (EGFR) in human breast cancer cell lines and induce cell cycle arrest and apoptosis [51,52]. In addition, it was shown that DIM treatment induced hyperpolarization of mitochondrial inner membrane, decreased cellular ATP level, and significantly stimulated mitochondrial reactive oxygen species (ROS) production.…”

Section: The Anti-cancer Effect Of Indole-diet Derivatives the Effectmentioning

confidence: 99%

The Anti-Carcinogenic Effect of Indole-3-Carbinol and 3, 3'-Diindolylmethane and their Mechanism of Action

Fares¹

2014

Med chem

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Indoles are aromatic heterocyclic organic compound and became the precursor to many pharmaceuticals. Indoles are found naturally in cruciferous plants and indole derivatives, indole-3-carbinole (I3C) and 3, 3'-diindolylmethane (DIM) can also be synthesized by a variety of methods. In vitro studies indicated that I3C and DIM inhibit cell proliferation, caused cell cycle arrest at G1 phase and induced apoptosis. The precise molecular mechanisms by which indole derivatives exert their tumor suppressive effects in human cancer cells are still unclear. It was reported that indoles alter estrogen metabolism. Microarray gene expression profiling and other studies indicated that indoles regulate many genes that are important for the control of cell cycle, cell proliferation, apoptosis, signal transduction, angiogenesis and cell invasion. In addition, it was found that indoles prevent tumor formation of breast and prostate cancer in animal models. Furthermore, these derivatives were evaluated in human clinical trials phase I and phase II as a potential chemopreventive agents against human breast, ovary, and vulvar intraepithelial neoplasia and colon cancers. Preliminary findings of these studies showed a significant clinical improvement. Interestingly, the use of indole derivatives was found to be safe without any indicated side effects. In conclusion, the results provide an evidence of the benefit of indole-derivatives in the prevention and treatment of hormone-dependent and hormone-independent human cancer. Further clinical trials are needed in order to approve the efficacy of indole derivatives in treatment of human cancer and to evaluate the indole use by the Food and Drug Administration (FDA).

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“…Although fairly high concentrations of some phytochemicals are appropriate in cells from tissues with high bioavailability (e.g., liver for I3C and DIM or colon for curcumin and EGCG), lower concentrations should be used for cells from tissues dependent on systemic bioavailability. Physiologically unrealistic concentrations have been used in many studies, including some of our own, to increase or hasten detection of end points (73,82,90 (90,91). Recent studies in breast cancer cells using EGCG (40-160 μg/mL = 87-351 μmol/L, which is borderline or toxic for normal breast cells) indicate that FOXO3 is involved in EGCG-induced cell death, reduced invasiveness, increased expression of E-cadherin and ERα, whereas further work from the same group suggests that EGCG may modulate E-cadherin expression via downregulation of CK2 and c-Rel signaling (92)(93)(94).…”

mentioning

confidence: 99%

Dietary Chemopreventive Phytochemicals: Too Little or Too Much?

Moiseeva

Manson

2009

Cancer Prevention Research

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There is a large body of evidence that the consumption of fruit and vegetables can decrease the risk of cancer. However, the link between diet and health is extremely complex. Some dietary phytochemicals seem to offer protection in an exposure-related manner and many molecular targets and signaling pathways affected by phytochemicals have been discovered. Although in vitro studies have contributed significantly to our understanding, quite a number use concentrations orders of magnitude greater than those achievable in humans or toxic to normal tissues (exemplified by toxic concentrations of indole-3-carbinol, epigallocatechin-3-gallate, curcumin, and genistein for breast cells). Such studies may produce results that are physiologically irrelevant, thus hindering predictions of efficacy. Here, we argue for careful consideration to be given to the in vitro experimental conditions under which dietary phytochemicals are investigated. Design features, such as the use of appropriate nontoxic concentrations, extended treatment times, three-dimensional cultures, primary tumor cultures, and comparison of susceptibility of various cancer subtypes, should improve our understanding of their molecular targets. This in turn would facilitate predictions as to their potential usefulness in the clinic. Chemopreventive Effect of Vegetables and FruitDiet is thought to contribute to a significant proportion of cancer cases and about a third of mortalities (1). Several international committees previously concluded that consumption of fruit and vegetables decreases the risk of cancer (2-4). More recently, the second WCRF-AICR report (5) found that overall, the evidence that vegetables and fruit protect against cancer is less impressive. However, among specific groups, Allium vegetables and garlic were considered to offer probable protection against stomach and colorectal cancers, respectively. Other groups, e.g., cruciferous vegetables [source of isothiocyanates (ITC) and indoles] or tea (source of polyphenols), received little attention in this report. The International Agency for Research on Cancer concluded that consumption of cruciferous vegetables is associated with a modest risk reduction for cancers at some sites, although the reductions are no greater than those observed with total vegetable uptake (6).Because of insufficient evidence, the conclusions of the latest WCRF-AICR report have somewhat undermined the hypothesis that specific phytochemicals, present in vegetables and fruit, may be responsible for chemoprevention. This lack of convincing evidence is partly because important contributing factors were not considered in many of the original studies. Many based on self-reporting are found to be biased. Factors, such as tobacco, gene polymorphisms, and body composition, can modify cancer risk (5). Significant differences in levels of consumed vegetables, and consequently dietary phytochemicals, are found among various populations. For example, the highest levels of cruciferous vegetable uptake in Europe and North A...

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Indole-3-carbinol-induced death in cancer cells involves EGFR downregulation and is exacerbated in a 3D environment

Cited by 20 publications

References 40 publications

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

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

The Anti-Carcinogenic Effect of Indole-3-Carbinol and 3, 3'-Diindolylmethane and their Mechanism of Action

Dietary Chemopreventive Phytochemicals: Too Little or Too Much?

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