1-Benzyl-indole-3-carbinol is a novel indole-3-carbinol derivative with significantly enhanced potency of anti-proliferative and anti-estrogenic properties in human breast cancer cells

Abstract

Indole-3-carbinol (I3C), a natural autolysis product of a gluccosinolate present in Brassica vegetables such as broccoli and cabbage, has anti-proliferative and anti-estrogenic activities in human breast cancer cells. A new and significantly more potent I3C analogue, 1-benzyl-I3C was synthesized, and in comparison to I3C, this novel derivative displayed an approximate 1000-fold enhanced potency in suppressing the growth of both estrogen responsive (MCF-7) and estrogen independent (MDA-MB-231) human breast cancer cells (I3C IC50 of 52 μM, and 1-benzyl-I3C IC50 of 0.05 μM). At significantly lower concentrations, 1-benzyl-I3C induced a robust G1 cell cycle arrest and elicited the key I3C-specific effects on expression and activity of G1 acting cell cycle genes including the disruption of endogenous interactions of the Sp1 transcription factor with the CDK6 promoter. Furthermore, in estrogen responsive MCF-7 cells, with enhanced potency 1-benzyl-I3C down regulated production of estrogen receptor-alpha protein, acts with tamoxifen to arrest breast cancer cell growth more effectively than either compound alone, and inhibited the in vivo growth of human breast cancer cell-derived tumor xenografts in athymic mice. Our results implicate 1-benzyl-I3C as a novel, potent inhibitor of human breast cancer proliferation and estrogen responsiveness that could potentially be developed into a promising therapeutic agent for the treatment of indole-sensitive cancers.

Metabolic Enzyme Sulfotransferase 1A1 Is the Trigger for N-Benzyl Indole Carbinol Tumor Growth Suppression

“…There is a literature precedent for the reactivity of I3C under acidic conditions, and this appears to translate to the benzylic analogs (Nguyen et al, 2010). We found that the compounds were stable in buffered aqueous environments.…”

“…Nguyen et al (2010) identified an N-benzyl derivative of I3C, which is a more potent analog of I3C in killing estrogenresponsive (MCF-7) and estrogen-independent (MDA-MB-231) human breast cancer cells. They further suggested that the parent and analogs are elastase inhibitors that disrupt cyclin E protein processing.…”

“…It is speculated to act in the estrogen pathway, although this claim is controversial. The N-BICs ( Figure 1A) differ from the parent I3C by virtue of having a benzyl group off of the indole nitrogen, rendering them more stable than the parent to acid (Aronchik et al, 2012;Nguyen et al, 2010).…”

Antiproliferative effects of artemisinin on human breast cancer cells requires the downregulated expression of the E2F1 transcription factor and loss of E2F1-target cell cycle genes

“…Chromatin immunoprecipitations were performed as previously described [26,27]. Briefly, cross-linking of proteins to DNA was obtained by the addition of formaldehyde at 1% of the final concentration for 5 min at room temperature to cultured cells.…”

Complementary/Alternative Medicine Strategies for Prevention and or Cure of Breast Cancer: A Review

“…It has been shown to sensitize breast cancer cells to tomoxifen, a chemotherapeutic drug used to treat breast cancer [21]. It also has been shown to inhibit bone metastasis of MDA-MB-231 breast cancer cells, in a mouse model [22].…”