Induction of growth arrest and apoptosis in human breast cancer cells by 3,3-diindolylmethane is associated with induction and nuclear localization of p27kip

Abstract

Abstract3,3 ¶-Diindolylmethane (DIM) is a stable condensation product of indole-3-carbanol, a potential breast cancer chemoprevention agent. Human breast cancer cell lines were studied to better understand its mechanisms.In vitro experiments were done in MCF-7, T47D, BT-20 and BT-474 cells using MTT, ELISA, immunoblotting assays, reverse transcription-PCR, protein half-life, confocal microscopy, cell fractionation, and immunoprecipitation assays. We found that DIM inhibited the growth of all four breast cancer cell lines (IC 50 s, 25-56 Mmol/L).

Chemopreventive properties of 3,3′-diindolylmethane in breast cancer: evidence from experimental and human studies

“…46 DIM has been shown to induce select tumor-suppressing proteins, including p21 and p27 kip , in cell culture. 53,54 In breast cancer cell lines that overexpress both human epidermal growth factor receptor 2 (Her2) and activated Akt, DIM exposure resulted in inhibition of activated Akt expression as well as independent induction of both p27 kip transcript expression and nuclear localization of p27 kip , ultimately resulting in apoptosis. 53 Apoptosis was also evident in Her2/neu-positive human breast cancer cells treated with a combination of DIM and paclitaxel, resulting in G 2 phase cell cycle arrest.…”

“…DIM selectively induced cell cycle arrest and apoptosis in both estrogen receptor-positive and estrogen receptor-negative breast cancer cells, without producing evidence of antiproliferative activity in normal breast epithelial cells. 53 The chemopreventive activity of DIM may have clinical applications in both hormone-dependent and hormone-independent disease. This may expand therapeutic options for triple-negative breast cancer.…”

Cell Cycle Regulatory Proteins in Breast Cancer: Molecular Determinants of Drug Resistance and Targets for Anticancer Therapies

“…Later, we reported genisteinmediated induction of p21 in ER-positive MCF-7 cells as well (Chinni et al, 2003). A similar activity of 3, 3'-Diindolylmethane (DIM; obtained from cruciferous vegetables) was also observed, and DIM was found to inhibit the expression of cyclin E2, survivin and Bcl-2, and induce the expression of p27 leading to the induction of cell cycle arrest and apoptosis in multiple breast cancer cell lines (Rahman et al, 2006;Wang et al, 2008). Effect of DIM on regulators of cell cycle (cyclin E2 and p21) as well as regulators of apoptotic pathways (survivin and Bcl-2) indicated a close connection and a mechanistic link between these pathways that may define the anticancer activity of natural compounds.…”

Indoles as anticancer agents

“…Many mechanisms of apoptosis stimulation of indole derivatives, I3C and DIM, were reported for, (a): down-regulation of anti-apoptotic gene products such as Bcl-2 (B-cell lymphoma 2) and Bcl-X L (B-cell leukemia-extra large), (b): down-regulation of the inhibitor of apoptosis proteins, e.g. CIAPs, X-chromosome linked inhibitor of apoptose protein (XIAP) and survival, (c): up-regulation of pro-apoptotic factors such as Bax gene, (d): liberation of mitochondrial cytochrome C in addition to stimulating of caspase-9 and caspase-3 [45] , and (e): inhibition of the NF-k B signaling pathway [46][47][48][49][50][51] . A vast number of diverse mechanisms of apoptosis induction by indoles have also been reported [52][53][54][55][56] .…”