ArticleProceedings of the National Academy of Sciences of the United States of America2008
The dietary phytochemical indole-3-carbinol is a natural elastase enzymatic inhibitor that disrupts cyclin E protein processing.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers, 2 of them syntheses that pooled it.
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Who cites it
27 citing papers in PubMed, 2 syntheses or guidelines pooled it, 63 citations in OpenAlex.
- Fruit and vegetable consumption and incident breast cancer: a systematic review and meta-analysis of prospective studies.British journal of cancer · 2021Pooled it
- Fruit and vegetable intake and risk of breast cancer by hormone receptor status.Journal of the National Cancer Institute · 2013Pooled it
- Planetary Health Diet Index and breast cancer risk.British journal of cancer · 2026Article
- 3,3'-Diindolylmethane (DIM): A Molecular Scaffold for Inhibition of WWP1 and WWP2, Members of the NEDD4 Family HECT E3 Ligases.ACS omega · 2025Article
- Natural Compounds as Protease Inhibitors in Therapeutic Focus on Cancer Therapy.Anti-cancer agents in medicinal chemistry · 2024Review
- Prevention of Alzheimer's disease through diet: An exploratory review.Metabolism open · 2023Review
- Synthetic Methodologies and Therapeutic Potential of Indole-3-Carbinol (I3C) and Its Derivatives.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Targeting eukaryotic proteases for natural products-based drug development.Natural product reports · 2020Review
- Plant natural modulators in breast cancer prevention: status quo and future perspectives reinforced by predictive, preventive, and personalized medical approach.The EPMA journal · 2018Review
- Indole-3-carbinol: a plant hormone combatting cancer.F1000Research · 2018Review
- Article
- Inhibition of oncogenic BRAF activity by indole-3-carbinol disrupts microphthalmia-associated transcription factor expression and arrests melanoma cell proliferation.Molecular carcinogenesis · 2017Article
- Cooperative antiproliferative signaling by aspirin and indole-3-carbinol targets microphthalmia-associated transcription factor gene expression and promoter activity in human melanoma cells.Cell biology and toxicology · 2016Article
- The antiproliferative response of indole-3-carbinol in human melanoma cells is triggered by an interaction with NEDD4-1 and disruption of wild-type PTEN degradation.Molecular cancer research : MCR · 2014Article
- Essential role of the cancer stem/progenitor cell marker nucleostemin for indole-3-carbinol anti-proliferative responsiveness in human breast cancer cells.BMC biology · 2014Article
- Indole-3-carbinol and its N-alkoxy derivatives preferentially target ERα-positive breast cancer cells.Cell cycle (Georgetown, Tex.) · 2014Article
- Mediterranean diet and cancer: epidemiological evidence and mechanism of selected aspects.BMC surgery · 2013Review
- Breast cancer cell uptake of the inflammatory mediator neutrophil elastase triggers an anticancer adaptive immune response.Cancer research · 2012Article
- Indole-3-carbinol synergistically sensitises ovarian cancer cells to bortezomib treatment.British journal of cancer · 2012Article
- Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Indole-3-carbinol (I3C), a naturally occurring component of Brassica vegetables, such as broccoli, cabbage, and Brussels sprouts, induces a G(1) cell-cycle arrest of human breast cancer cells, although the direct cellular targets that mediate this process are unknown. Treatment of highly invasive MDA-MB-231 breast cancer cells with I3C shifted the stable accumulation of cyclin E protein from the hyperactive lower-molecular-mass 35-kDa form that is associated with cancer cell proliferation and poor clinical outcomes to the 50-kDa cyclin E form that typically is expressed in normal mammary tissue. An in vitro cyclin E processing assay, in combination with zymography, demonstrated that I3C, but not its natural dimer, 3,3'-diindolylmethane, disrupts proteolytic processing of the 50-kDa cyclin E into the lower-molecular-mass forms by direct inhibition of human neutrophil elastase enzymatic activity. Analysis of elastase enzyme kinetics using either cyclin E or N-methoxysuccinyl-Ala-Ala-Pro-Val-p-nitroanalide as substrates demonstrated that I3C acts as a noncompetitive inhibitor of elastase activity with an inhibitory constant of approximately 12 microM. Finally, siRNA ablation of neutrophil elastase protein production in MDA-MB-231 cells mimicked the I3C-disrupted processing of the 50-kDa cyclin E protein and the indole-induced cell-cycle arrest. Taken together, our results demonstrate that elastase is the first identified specific target protein for I3C and that the direct I3C inhibition of elastase enzymatic activity implicates the potential use of this indole, or related compounds, in targeted therapies of human breast cancers where high elastase levels are correlated with poor prognosis.
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