Molecular Targets and Anticancer Potential of Indole-3-Carbinol and Its Derivatives

Abstract

Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=1993 KEY WORDSI3C ReviewMolecular Targets and Anticancer Potential of Indole-3-Carbinol and Its Derivatives ABSTRACT Indole-3-carbinol (I3C) is produced by members of the family Cruciferae, and particularly members of the genus Brassica (e.g., cabbage, radishes, cauliflower, broccoli, Brussels sprouts, and daikon). Under acidic conditions, I3C is converted to a series of oligomeric products (among which 3,3'-diindolylmethane is a major component) thought to be responsible for its biological effects in vivo. In vitro, I3C has been shown to suppress the proliferation of various tumor cells including breast cancer, prostate cancer, endometrial cancer, colon cancer and leukemic cells; induce G 1 /S arrest of the cell cycle and induce apoptosis. The cell cycle arrest involves downregulation of cyclin D1, cyclin E, cyclin-dependent kinase (CDK)2, CDK4 and CDK6 and upregulation of p15, p21 and p27. Apoptosis by I3C involves downregulation antiapoptotic gene products, including Bcl-2, Bcl-xL, survivin, inhibitor-of-apoptosis protein (IAP), X chromosome-linked IAP (XIAP), and Fas-associated death domain protein-like interleukin-1-β-converting enzyme inhibitory protein (FLIP); upregulation of proapoptotic protein Bax; release of micochondrial cytochrome C; and activation of caspase-9 and caspase-3. This agent inhibits the activation of various transcription factors including nuclear factor-kappaB, SP1, estrogen receptor, androgen receptor and nuclear factor-E2-related factor 2 (Nrf2). This indole potentiates the effects of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through induction of death receptors and synergises with chemotherapeutic agents through downregulation of P-glycoprotein (P-gp). In vivo, I3C was found to be a potent chemopreventive agent for hormonal-dependent cancers such as breast and cervical cancer. These effects are mediated through its ability to induce apoptosis, inhibit DNA-carcinogen adduct formation, and suppress free-radical production, stimulate 2-hydroxylation of estradiol, inhibit invasion and angiogenesis. Numerous studies have indicated that I3C also has a strong hepatoprotective activity against various carcinogens. Initial clinical trials in women have shown that I3C is a promising agent against breast and cervical cancers.

N-Alkoxy derivatization of indole-3-carbinol increases the efficacy of the G1 cell cycle arrest and of I3C-specific regulation of cell cycle gene transcription and activity in human breast cancer cells

“…The consumption of Brassica vegetables is directly associated with decreased risk of various cancers in human subjects and reduced tumor incidence in experimental animals [6,11]. We previously established that I3C, which is one the major active compounds in Brassica vegetables, induces a G1 cell cycle arrest of human breast cancer cell lines through a cellular pathway that leads to the down-regulation of CDK6 transcription and inhibition of CDK2 kinase activity [10,27,29,30].…”

“…These studies suggest that dietary plants produce unique compounds that represent a largely untapped source of potentially potent chemotherapeutic molecules. One such phytochemical is indole-3-carbinol (I3C), a naturally occurring component of Brassica vegetables, such as cabbage, broccoli, and Brussels sprouts [8][9][10][11][12].…”

“…When ingested, the low pH of the stomach converts I3C into several products, including the diindole products indole [3,2-b]carbazole (ICZ) and 3,3′-diindolylmethane (DIM), and the trimerization product 5,6,11,12,17,18-hexahydrocyclonona [1,2-b:4,5-b′:7,8b″]triindole (CTr) [11,[18][19][20][21][22]. A general picture has emerged that a subset of these acid-catalyzed products have distinct anti-proliferative and anti-tumorigenic physiological bioactivities.…”

Diazoxide-Mediated Growth Inhibition in Human Lung Cancer Cells via Downregulation of β-Catenin-Mediated Cyclin D1 Transcription

“…b-Catenin is a well-known DNAbinding nuclear protein that is widely expressed in tissues and binds to GC box motifs in promoters of many housekeeping genes and genes involved in growth regulation and cancer, including p21, caspase-8, Cyclin D1, and GalT V [24][25][26]. Biologically, b-catenin plays important roles in a wide variety of physiologic processes, including cell cycle, hormonal activation, apoptosis, angiogenesis, and oncogenesis [24,27].…”

Indole-3-carbinol (I3C) increases apoptosis, represses growth of cancer cells, and enhances adenovirus-mediated oncolysis

“…13 Limited and inconclusive studies suggest that I3C may have anticarcinogenic properties in a wide range of cancers; thus it is used as a dietary supplement in the hope of cancer prevention. [14][15][16][17] In the present study, we investigate the effect of I3C on cancer cell growth and Ad oncolytic replication. We observed that high doses of I3C induced cancer cell apoptosis and that low doses of Indole-3-carbinol (I3C) increases apoptosis, represses growth of cancer cells, and enhances adenovirus-mediated oncolysis epidemiological studies suggest that high intake of cruciferous vegetables is associated with a lower risk of cancer.…”