Indole-3-carbinol (I3C),
autolysis product of
glucosinolates present in cruciferous vegetables, has been indicated as a promising agent in preventing the development and progression of
breast cancer. I3C has been shown to inhibit the growth of human
cancer cells in vitro and possesses anticarcinogenic activity in vivo. Because I3C is unstable and may be converted into many polymeric products in the digestive tract, it is not yet clear whether the
biological activity observed can be attributed to I3C or some of its polymeric products. In this study we synthesized a stable I3C cyclic tetrameric derivative and investigated its effects on a panel of human
breast cancer cell lines. The I3C tetramer suppressed the growth of both
estrogen receptor (ER) -positive (MCF-7, 734B, and BT474) and ER-negative (BT20, MDA-MB-231, and BT539) human
breast cancer cell lines, and it was found to induce G(1) cell cycle arrest in a dose-dependent manner without evidence of apoptosis, suggesting a growth arrest via a
cytostatic mechanism. At the molecular level, the tetramer inhibited
cyclin-dependent kinase (CDK) 6 expression and activity, induced an increase in the level of p27(kip1), and reduced the level of
retinoblastoma protein expression. Contrarily to CDK6, the level of CDK4, the other
kinase involved in the G(1) phase of the cell cycle, remains unchanged. Interestingly, the tetramer resulted about five times more active than I3C in suppressing the growth of human
breast cancer cells. On the whole, our data suggest that the I3C tetrameric derivative is a novel lead inhibitor of
breast cancer cell growth that may be a considered a new, promising therapeutic agent for both ER+ and ER-
breast cancer.