Indole-3-carbinol

Last updated
Indole-3-carbinol [1]
Indole-3-carbinol.png
Names
Preferred IUPAC name
(1H-Indol-3-yl)methanol
Other names
Indole-3-carbinol; 3-Indolylcarbinol; 1H-Indole-3-methanol; 3-Hydroxymethylindole; 3-Indolemethanol; Indole-3-methanol; I3C
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.010.762 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 211-836-2
PubChem CID
RTECS number
  • NL9483000
UNII
  • InChI=1S/C9H9NO/c11-6-7-5-10-9-4-2-1-3-8(7)9/h1-5,10-11H,6H2 Yes check.svgY
    Key: IVYPNXXAYMYVSP-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C9H9NO/c11-6-7-5-10-9- 4-2-1-3-8(7)9/h1-5,10-11H,6H2
  • InChI=1/C9H9NO/c11-6-7-5-10-9-4-2-1-3-8(7)9/h1-5,10-11H,6H2
    Key: IVYPNXXAYMYVSP-UHFFFAOYAO
  • OCc2c1ccccc1[nH]c2
Properties
C9H9NO
Molar mass 147.177 g·mol−1
AppearanceOff-white solid
Melting point 96 to 99 °C (205 to 210 °F; 369 to 372 K)
Partially in cold water[ vague ]
Hazards
GHS labelling: [2]
GHS-pictogram-exclam.svg
Warning
H315, H319
P305+P351+P338
NFPA 704 (fire diamond)
NFPA 704.svgHealth 1: Exposure would cause irritation but only minor residual injury. E.g. turpentineFlammability 0: Will not burn. E.g. waterInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
1
0
0
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Indole-3-carbinol (I3C, C 9 H 9 N O) is produced by the breakdown of the glucosinolate glucobrassicin, which can be found at relatively high levels in cruciferous vegetables such as broccoli, cabbage, cauliflower, brussels sprouts, collard greens and kale. It is also available in dietary supplements. [3] Indole-3-carbinol is the subject of on-going biomedical research into its possible anticarcinogenic, [4] antioxidant, and anti-atherogenic effects. [5] Research on indole-3-carbinol has been conducted primarily using laboratory animals and cultured cells. [6] Limited and inconclusive human studies have been reported. A recent review of the biomedical research literature found that "evidence of an inverse association between cruciferous vegetable intake and breast or prostate cancer in humans is limited and inconsistent" and "larger randomized controlled trials are needed" to determine if supplemental indole-3-carbinol has health benefits. [7]

Contents

Indole-3-carbinol and cancer

Investigation of mechanisms by which consumption of indole-3-carbinol might influence cancer incidence focuses on its ability to alter estrogen metabolism and other cellular effects. Controlled studies have been performed on such animals as rats, mice, and rainbow trout, introducing various controlled levels of carcinogens, and levels of indole-3-carbinol into their daily diet. Results showed dose-related decreases in tumor susceptibility due to indole-3-carbinol (inferred by decreases in aflatoxin–DNA binding). The first direct evidence of pure anti-initiating activity by a natural anticarcinogen (indole-3-carbinol) found in human diet was claimed by Dashwood et al. in 1989. [8]

Indole-3-carbinol induces a G1 growth arrest of human reproductive cancer cells. [9] This is potentially relevant to the prevention and treatment of cancer, as the G1 phase of cell growth occurs early in the cell life cycle, and, for most cells, is the major period of cell cycle during its lifespan. The G1 phase is marked by synthesis of various enzymes that are required in the next ("S") phase, including those needed for DNA replication.

Overuse of indole-3-carbinol supplements in the hope of preventing cancer may be unwise, as the hormone balance should be tested (via simple blood test) before regular consumption. Such caution is advised, due to its effect on estrogen levels (estrogen has a significant impact on brain function). [10] [11]

It promotes liver cancer in trout when it is combined with aflatoxin B1 and demotes metastasis. [6]

Melanoma

Indole-3-carbinol causes proliferation arrest and apoptosis in human melanoma cells. Kim et al. (2011) showed that the master regulator of melanoma biology, microphthalmia-associated transcription factor (MITF-M) was downregulated by indole-3-carbinol to induce apoptosis. [12] Kundu et al. (2017) demonstrated that the anticancer property of indole-3-carbinol is driven by specific targeting of oncogenic pathways. [13] [14] In two different studies using xenografted mouse model of melanoma, they observed that subcutaneous injection of indole-3-carbinol could bring down tumor burden significantly. The underlying molecular mechanism of this anti-tumor effect was found to be by the specific inhibition of activity of oncogenic BRAF V600E in tumors that harbored the mutation. However, in tumors that expressed wild type BRAF, indole-3-carbinol did not cause any comparable antiproliferative effect. Additionally indole-3-carbinol did not cause antiproliferation even in normal epidermal melanocytes underscoring the specificity and selectivity of its action. Kundu et al.[ citation needed ] further showed that inhibition of BRAF V600E activity by indole-3-carbinol resulted in downregulation of MITF-M by downstream signaling which caused a G1 cell cycle arrest leading to the observed antiproliferative effect.

In a second study Kundu et al.[ citation needed ] showed that in melanoma cells where PTEN is downregulated, indole-3-carbinol directly interacts with NEDD41 to prevent PTEN ubiquitination and subsequent proteasomal degradation. This results in stabilization of PTEN and inhibition of proliferation by downstream AKT signaling. Overall scientific evidence shows that in melanoma, indole-3-carbinol specifically inhibits the two most commonly associated driver mutation signaling pathways to cause proliferation, a fact that can be used to design clinical trial to treat human patients with indole-3-carbinol in future.

Systemic lupus erythematosus

Indole-3-carbinol can shift estrogen metabolism towards less estrogenic metabolites. Systemic lupus erythematosus (SLE, or lupus), an autoimmune disease, is associated with estrogen. In a study using mice bred to develop lupus, indole-3-carbinol was fed to one group while another group was fed a standard mouse diet; the group fed the indole-3-carbinol diet lived longer and had fewer signs of disease. [15]

Another study of lupus-prone mice with indole-3-carbinol defined the mechanism for the improvement of their disease to be due to sequential blocks in the development of B and T cells of these mice. The maturation arrests resulted in a fall in autoantibody production, thought to be a crucial component of lupus causation. In addition, I3C supplementation of the disease prone mice led to a normalization of their T cell function. [16]

Women with lupus can manifest a metabolic response to indole-3-carbinol and might also benefit from its antiestrogenic effects. Clinical trials are currently underway to determine the efficacy of treating human patients with lupus using indole-3-carbinol.

Effect in recurrent respiratory papillomatosis

There is evidence suggesting that indole-3-carbinol may have an effect on human papillomavirus-infected cells in both pediatrics and adult patients. [17] [18] Research is ongoing.

Related Research Articles

<span class="mw-page-title-main">Melanoma</span> Cancer originating in melanocytes

Melanoma, also redundantly known as malignant melanoma, is a type of cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye. In women, they most commonly occur on the legs, while in men, they most commonly occur on the back. About 25% of melanomas develop from moles. Changes in a mole that can indicate melanoma include an increase in size, irregular edges, change in color, itchiness, or skin breakdown.

<span class="mw-page-title-main">3,3'-Diindolylmethane</span> Chemical compound

3,3′-Diindolylmethane (DIM) is a compound derived from the digestion of indole-3-carbinol, found in cruciferous vegetables, such as broccoli, Brussels sprouts, cabbage and kale. It and its parent compound – indole-3-carbinol – are under laboratory research to determine their possible biological properties, particularly in anti-cancer mechanisms. DIM is sold as a dietary supplement.

<i>PTEN</i> (gene) Tumor suppressor gene

Phosphatase and tensin homolog (PTEN) is a phosphatase in humans and is encoded by the PTEN gene. Mutations of this gene are a step in the development of many cancers, specifically glioblastoma, lung cancer, breast cancer, and prostate cancer. Genes corresponding to PTEN (orthologs) have been identified in most mammals for which complete genome data are available.

<span class="mw-page-title-main">Microphthalmia-associated transcription factor</span> Mammalian protein found in Homo sapiens

Microphthalmia-associated transcription factor also known as class E basic helix-loop-helix protein 32 or bHLHe32 is a protein that in humans is encoded by the MITF gene.

<span class="mw-page-title-main">Endometrial intraepithelial neoplasia</span>

Endometrial intraepithelial neoplasia (EIN) is a premalignant lesion of the uterine lining that predisposes to endometrioid endometrial adenocarcinoma. It is composed of a collection of abnormal endometrial cells, arising from the glands that line the uterus, which have a tendency over time to progress to the most common form of uterine cancer—endometrial adenocarcinoma, endometrioid type.

<span class="mw-page-title-main">CD133</span> Protein-coding gene in the species Homo sapiens

CD133 antigen, also known as prominin-1, is a glycoprotein that in humans is encoded by the PROM1 gene. It is a member of pentaspan transmembrane glycoproteins, which specifically localize to cellular protrusions. When embedded in the cell membrane, the membrane topology of prominin-1 is such that the N-terminus extends into the extracellular space and the C-terminus resides in the intracellular compartment. The protein consists of five transmembrane segments, with the first and second segments and the third and fourth segments connected by intracellular loops while the second and third as well as fourth and fifth transmembrane segments are connected by extracellular loops. While the precise function of CD133 remains unknown, it has been proposed that it acts as an organizer of cell membrane topology.

<span class="mw-page-title-main">Insulin receptor substrate 1</span> Protein-coding gene in the species Homo sapiens

Insulin receptor substrate 1(IRS-1) is a signaling adapter protein that in humans is encoded by the IRS1 gene. It is a 131 kDa protein with amino acid sequence of 1242 residues. It contains a single pleckstrin homology (PH) domain at the N-terminus and a PTB domain ca. 40 residues downstream of this, followed by a poorly conserved C-terminus tail. Together with IRS2, IRS3 (pseudogene) and IRS4, it is homologous to the Drosophila protein chico, whose disruption extends the median lifespan of flies up to 48%. Similarly, Irs1 mutant mice experience moderate life extension and delayed age-related pathologies.

<span class="mw-page-title-main">BRAF (gene)</span> Protein-coding gene in the species Homo sapiens

BRAF is a human gene that encodes a protein called B-Raf. The gene is also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B, while the protein is more formally known as serine/threonine-protein kinase B-Raf.

<span class="mw-page-title-main">RAB7A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rab-7a is a protein that in humans is encoded by the RAB7A gene.

<span class="mw-page-title-main">GPR56</span> Protein-coding gene in the species Homo sapiens

G protein-coupled receptor 56 also known as TM7XN1 is a protein encoded by the ADGRG1 gene. GPR56 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">PMEL (gene)</span> Protein-coding gene in the species Homo sapiens

Melanocyte protein PMEL also known as premelanosome protein (PMEL), silver locus protein homolog (SILV) or Glycoprotein 100 (gp100), is a protein that in humans is encoded by the PMEL gene. Its gene product may be referred to as PMEL, silver, ME20, gp100 or Pmel17.

<span class="mw-page-title-main">Programmed cell death protein 1</span> Mammalian protein found in Homo sapiens

Programmed cell death protein 1(PD-1),. PD-1 is a protein encoded in humans by the PDCD1 gene. PD-1 is a cell surface receptor on T cells and B cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.

<span class="mw-page-title-main">DDX3X</span> Protein-coding gene in humans

ATP-dependent RNA helicase DDX3X is an enzyme that in humans is encoded by the DDX3X gene.

<span class="mw-page-title-main">MLANA</span> Protein-coding gene in the species Homo sapiens

Protein melan-A also known as melanoma antigen recognized by T cells 1 or MART-1 is a protein that in humans is encoded by the MLANA or "MALENA" gene. A fragment of the protein, usually consisting of the nine amino acids 27 to 35, is bound by MHC class I complexes which present it to T cells of the immune system. These complexes can be found on the surface of melanoma cells. Decameric peptides (26-35) are being investigated as cancer vaccines.

<span class="mw-page-title-main">LZTS1</span> Protein-coding gene in the species Homo sapiens

Leucine zipper putative tumor suppressor 1 is a protein that, in humans, is encoded by the LZTS1 gene.

<span class="mw-page-title-main">Vemurafenib</span> Targeted cancer drug

Vemurafenib (INN), sold under the brand name Zelboraf, is a medication used for the treatment of late-stage melanoma. It is an inhibitor of the B-Raf enzyme and was developed by Plexxikon.

In molecular biology, competing endogenous RNAs regulate other RNA transcripts by competing for shared microRNAs (miRNAs). Models for ceRNA regulation describe how changes in the expression of one or multiple miRNA targets alter the number of unbound miRNAs and lead to observable changes in miRNA activity - i.e., the abundance of other miRNA targets. Models of ceRNA regulation differ greatly. Some describe the kinetics of target-miRNA-target interactions, where changes in the expression of one target species sequester one miRNA species and lead to changes in the dysregulation of the other target species. Others attempt to model more realistic cellular scenarios, where multiple RNA targets are affecting multiple miRNAs and where each target pair is co-regulated by multiple miRNA species. Some models focus on mRNA 3' UTRs as targets, and others consider long non-coding RNA targets as well. It's evident that our molecular-biochemical understanding of ceRNA regulation remains incomplete.

Gopal Chandra Kundu is an Indian cell and cancer biologist and a Senior Scientist (Scientist-G) at National Centre for Cell Science. He is known for his contributions towards the understanding the mechanism of cancer progression in breast, melanoma and other cancers and development of novel therapeutic targets and target-based therapy in cancers.

V600E is a mutation of the BRAF gene in which valine (V) is substituted by glutamic acid (E) at amino acid 600. It is a driver mutation in a proportion of certain diagnoses, including melanoma, hairy cell leukemia, papillary thyroid carcinoma, colorectal cancer, non-small-cell lung cancer, Langerhans cell histiocytosis, Erdheim–Chester disease and ameloblastoma.

References

  1. ↑ Data at chemblink.com
  2. ↑ GHS: Sigma-Aldrich i7256
  3. ↑ Sarubin-Fragakis, A.; Thomson, C.; American Dietetic Association (2007). The Health Professional's Guide to Popular Dietary Supplements. American Dietetic Association. p. 312. ISBN   9780880913638.
  4. ↑ Park, N. I.; Kim, J. K.; Park, W. T.; Cho, J. W.; Lim, Y. P.; Park, S. U. (2010). "An efficient protocol for genetic transformation of watercress (Nasturtium officinale) using Agrobacterium rhizogenes". Molecular Biology Reports. 38 (8): 4947–4953. doi:10.1007/s11033-010-0638-5. PMID   21161399. S2CID   19612120.
  5. ↑ "indole-3-methanol (CHEBI:24814)". Chemical Entities of Biological Interest (ChEBI). European Bioinformatics Institute. Retrieved 2016-03-25.
  6. 1 2 Tilton, S. C.; Hendricks, J. D.; Orner, G. A.; Pereira, C. B.; Bailey, G. S.; Williams, D. E. (2007). "Gene expression analysis during tumor enhancement by the dietary phytochemical, 3,3′-diindolylmethane, in rainbow trout". Carcinogenesis. 28 (7): 1589–1598. doi: 10.1093/carcin/bgm017 . PMID   17272308.
  7. ↑ Higdon, J.; Delage, B.; Williams, D.; Dashwood, R. (2007). "Cruciferous vegetables and human cancer risk: Epidemiologic evidence and mechanistic basis". Pharmacological Research. 55 (3): 224–236. doi:10.1016/j.phrs.2007.01.009. PMC   2737735 . PMID   17317210.
  8. ↑ Dashwood, R. H.; Arbogast, D. N.; Fong, A. T.; Pereira, C.; Hendricks, J. D.; Bailey, G. S. (1989). "Quantitative inter-relationships between aflatoxin B1 carcinogen dose, indole-3-carbinol anti-carcinogen dose, target organ DNA adduction and final tumor response". Carcinogenesis. 10 (1): 175–181. doi:10.1093/carcin/10.1.175. PMID   2491968.
  9. ↑ Hsu, J.; Dev, A.; Wing, A.; Brew, C.; Bjeldanes, L.; Firestone, G. (2006). "Indole-3-carbinol mediated cell cycle arrest of LNCaP human prostate cancer cells requires the induced production of activated p53 tumor suppressor protein". Biochemical Pharmacology . 72 (12): 1714–1723. doi:10.1016/j.bcp.2006.08.012. PMID   16970927.
  10. ↑ Culmsee, C.; Vedder, H.; Ravati, A.; Junker, V.; Otto, D.; Ahlemeyer, B.; Krieg, J.-C.; Krieglstein, J. (1999). "Neuroprotection by Estrogens in a Mouse Model of Focal Cerebral Ischemia and in Cultured Neurons: Evidence for a Receptor-Independent Antioxidative Mechanism". Journal of Cerebral Blood Flow & Metabolism. 19 (11): 1263–1269. doi: 10.1097/00004647-199911000-00011 . PMID   10566973.
  11. ↑ "Estrogen's Influence on the Brain". Society for Neuroscience.
  12. ↑ Kim, S.-Y.; Kim, D.-S.; Jeong, Y.-M.; Moon, S.-I.; Kwon, S.-B.; Park, K.-C. (2011). "Indole-3-carbinol and ultraviolet B induce apoptosis of human melanoma cells via down-regulation of MITF". Pharmazie. 66 (12): 982–987. PMID   22312706.
  13. ↑ Kundu, A.; Quirit, J. G.; Khouri, M. G.; Firestone, G. L. (2017). "Inhibition of oncogenic BRAF activity by indole-3-carbinol disrupts microphthalmia-associated transcription factor expression and arrests melanoma cell proliferation". Molecular Carcinogenesis. 56 (1): 49–61. doi:10.1002/mc.22472. PMC   4985490 . PMID   26878440.
  14. ↑ Kundu, A.; Aronchik, I.; Quirit, J. G.; Firestone, G. L. (2014). "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. 12 (11): 1621–1634. doi:10.1158/1541-7786.MCR-14-0018. PMC   4233179 . PMID   25009292.
  15. ↑ Auborn, K. J.; Qi, M.; Yan, X.-J.; Teichberg, S.; Chen, D.; Madaio, M. P.; Chiorazzi, N. (2003). "Lifespan is prolonged in autoimmune-prone (NZB/NZW) F1 mice fed a diet supplemented with indole-3-carbinol". The Journal of Nutrition. 133 (11): 3610–3613. doi: 10.1093/jn/133.11.3610 . PMID   14608082.
  16. ↑ Yan, X.-J.; Qi, M.; Telusma, G.; Yancopoulos, S.; Madaio, M.; Satoh, M.; Reeves, W. H.; Teichberg, S.; et al. (2009). "Indole-3-carbinol improves survival in lupus-prone mice by inducing tandem B- and T-cell differentiation blockades". Clinical Immunology. 131 (3): 481–494. doi:10.1016/j.clim.2009.01.013. PMID   19278904.
  17. ↑ Rosen, C. A.; Bryson, P. C. (2004). "Indole-3-Carbinol for recurrent respiratory papillomatosis: Long-term results". Journal of Voice. 18 (2): 248–253. doi:10.1016/j.jvoice.2003.05.005. PMID   15193659.
  18. ↑ Rosen, C. A.; Woodson, G. E.; Thompson, J. W.; Hengesteg, A. P.; Bradlow, H. L. (1998). "Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis". Otolaryngology–Head and Neck Surgery. 118 (6): 810–815. doi:10.1016/S0194-5998(98)70274-8. PMID   9627242. S2CID   370098.

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