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. Melanoma Indole-3-carbinol causes proliferation arrest and apoptosis in human melanoma cells. Kim YS et al showed that the master regulator of melanoma biology, microphthalmia-associated transcription factor (MITF-M) was downregulated by indole-3-carinol to induce apoptosis. Kundu A et al demonstrated that the anticancer property of indole-3-carbinol is driven by specific targeting of oncogenic pathways. 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 BRAFV600E 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  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  showed that in melanoma cells where PTEN is downregulated, indole-3-carbinol directly interacts with NEDD4_1 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. 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.
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. 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-carinol to induce apoptosis. Kundu et al. (2017) demonstrated that the anticancer property of indole-3-carbinol is driven by specific targeting of oncogenic pathways. 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 BRAFV600E 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 . 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 . 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. 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.
R
aflatoxin-DNA
aflatoxin–DNA
D
,
D
,
R
YS et al
et al. (2011)
R
A et al
et al. (2017)
A
.
A
.
R
NEDD4_1
NEDD41
R
lupus prone
lupus-prone