Abstract
Indole-3-carbinol (I3C) and diindolylmethane (DIM), found in cruciferous vegetables, have chemopreventive and anticancer properties. In the present study, 14 substituted indoles were tested for activity against SW480 colon cancer cells. Among these, 3-(2-bromoethyl)-indole, named BEI-9, showed the greatest inhibition. The effects of BEI-9 on cancer cells were analyzed by MTS and CellTiter-Glo assays for effects on cell viability, by microscopy for phenotypic changes, by scratch wound assays for effects on migration, by flow cytometry for changes in the cell cycle, by immunoblotting for cyclin D and A to assess effects on cell cycle regulation, and by NF-κB reporter assays for effects on basal and drug-induced NF-κB activation. BEI-9 inhibited the growth of SW480 and HCT116 colon cancer cells at concentrations of 12.5 and 5 µM, respectively. BEI-9 also inhibited cell motility as determined with scratch wound assays, and reduced the levels of cyclin D1 and A. Furthermore, in reporter cells, BEI-9 (0.8 µM) inhibited basal and induced NF-κB activation and increased cell death when combined with the cytokine TNFα or the drug camptothecin (CPT), both of which activate NF-κB. Preliminary experiments to identify a safe dose range for immunodeficient mice showed that BEI-9, administered intraperitoneally, was tolerable at doses below 10 mg/kg. Thus, BEI-9 and other indole derivatives may be useful in chemoprevention or as chemosensitizers. Since NF-κB activation is implicated in carcinogenesis and in reducing sensitivity to anticancer drugs, BEI-9 should be investigated in combination with drugs such as CPT, which activate NF-κB.
Highlights
The indole chemical moiety is a backbone for several bioactive compounds including the amino acid tryptophan, the signaling compound melatonin, the nutritional compound indole‐3-carbinol (I3C), and several receptor or kinase agonists or antagonists
Since NF-κB activation is implicated in carcinogenesis and in reducing sensitivity to anticancer drugs, BEI-9 should be investigated in combination with drugs such as CPT, which activate NF-κB
Since NF-κB activation is implicated in carcinogenesis and in reducing sensitivity to anticancer drugs, BEI-9 should be investigated in combination with drugs, such as CPT and docetaxel, which activate NF-κB [23,30-32]
Summary
The indole chemical moiety is a backbone for several bioactive compounds including the amino acid tryptophan, the signaling compound melatonin, the nutritional compound indole‐3-carbinol (I3C), and several receptor or kinase agonists or antagonists. Upon exposure to acidic environments, such as that in the stomach, I3C is converted into derivatives with variable stability and bioactivity [3]. Indole compounds have potential as chemopreventive and chemotherapeutic agents. Cellular targets identified for natural or derivatized indole compounds include PPARγ and Nur77 [6], transcription factors [7-10], cyclin-dependent kinase (CDK) complexes [11,12], PKB/Akt [13,14], and hormone receptors [15,16]. Indole compounds have activity against colon cancer cells, suggesting their potential use in chemoprevention or therapy [17-20]. A full description of cellular targets and potential mechanisms of actions of indole compounds is available [21,22]
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