Abstract
Background3,3'-Diindolylmethane (DIM), an indole derivative produced in the stomach after the consumption of broccoli and other cruciferous vegetables, has been demonstrated to exert anti-cancer effects in both in vivo and in vitro models. We have previously determined that DIM (0 – 30 μmol/L) inhibited the growth of HT-29 human colon cancer cells in a concentration-dependent fashion. In this study, we evaluated the effects of DIM on cell cycle progression in HT-29 cells.MethodsHT-29 cells were cultured with various concentrations of DIM (0 – 30 μmol/L) and the DNA was stained with propidium iodide, followed by flow cytometric analysis. [3H]Thymidine incorporation assays, Western blot analyses, immunoprecipitation and in vitro kinase assays for cyclin-dependent kinase (CDK) and cell division cycle (CDC)2 were conducted.ResultsThe percentages of cells in the G1 and G2/M phases were dose-dependently increased and the percentages of cells in S phase were reduced within 12 h in DIM-treated cells. DIM also reduced DNA synthesis in a dose-dependent fashion. DIM markedly reduced CDK2 activity and the levels of phosphorylated retinoblastoma proteins (Rb) and E2F-1, and also increased the levels of hypophosphorylated Rb. DIM reduced the protein levels of cyclin A, D1, and CDK4. DIM also increased the protein levels of CDK inhibitors, p21CIP1/WAF1 and p27KIPI. In addition, DIM reduced the activity of CDC2 and the levels of CDC25C phosphatase and cyclin B1.ConclusionHere, we have demonstrated that DIM induces G1 and G2/M phase cell cycle arrest in HT-29 cells, and this effect may be mediated by reduced CDK activity.
Highlights
Epidemiologic data continue to support the hypothesis that the intake of Brassica plants, including turnips, kale, broccoli, cabbage, Brussels sprouts, and cauliflower, may exert protective effects against various types of cancers [14]
We have previously demonstrated that DIM inhibits the growth of HT-29 and HCT-116 human colon cancer cells and induced apoptosis in these cells [31]
DIM induces cell cycle arrest at the G1 and G2/M phases and inhibits DNA synthesis in HT-29 cells We have previously shown that DIM reduces the numbers of viable HT-29 cells in a dose-dependent manner (10 – 30 μmol/L) [31]
Summary
Epidemiologic data continue to support the hypothesis that the intake of Brassica plants, including turnips, kale, broccoli, cabbage, Brussels sprouts, and cauliflower, may exert protective effects against various types of cancers [14]. Indole-3-carbinol (I3C) is the principal hydrolysis product of the glucosinolate glucobrassicin [7], and has been shown to offer significant protection against cancer in animal models induced by a variety of chemical carcinogens [8,9,10], as well as in cultured human cancer cells [11,12,13]. It has been shown that DIM reduces carcinogenesis in a variety of animal cancer models, including the tumor growth of injected TRAMP-C2, a mouse prostate cell line, in C57BL/6 mice [19], 7,12-dimethylbenz [a]anthracene (DMBA)-induced mammary tumors in rats [20], benzo [a]pyrene-induced stomach cancers in mice, and the growth of transplantable human breast carcinoma and angiogenesis in mice [21]. Results generated with in vitro cell culture studies have shown that DIM inhibits the proliferation of a variety of cancer cell types, including prostate (Reviewed in [22]) and breast [23,24] cancer cells, via the induction of cell cycle arrest and apoptosis
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