This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brandi, G. Articles by Magnani, M. Search for Related Content PubMed PubMed Citation Articles by Brandi, G. Articles by Magnani, M.

A New Indole-3-Carbinol Tetrameric Derivative Inhibits Cyclin-dependent Kinase 6 Expression, and Induces G₁ Cell Cycle Arrest in Both Estrogen-dependent and Estrogen-independent Breast Cancer Cell Lines¹

Institutes of Biochemestry "G. Fornaini" [M. P., B. C., M. M.], Hygiene [G. B.], and Organic Chemistry [C. F., P. F.], University of Urbino, 61029 Urbino, and Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan [C. D. M., N. Z.], Italy

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 G₁ 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 G₁ 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.

This article has been cited by other articles:

				J.-R. Weng, C.-H. Tsai, S. K. Kulp, D. Wang, C.-H. Lin, H.-C. Yang, Y. Ma, A. Sargeant, C.-F. Chiu, M.-H. Tsai, et al. A Potent Indole-3-Carbinol Derived Antitumor Agent with Pleiotropic Effects on Multiple Signaling Pathways in Prostate Cancer Cells Cancer Res., August 15, 2007; 67(16): 7815 - 7824. [Abstract] [Full Text] [PDF]

				N. M. Probst-Hensch, C.-L. Sun, D. V. D. Berg, M. Ceschi, W.-P. Koh, and M. C. Yu The effect of the cyclin D1 (CCND1) A870G polymorphism on colorectal cancer risk is modified by glutathione-S-transferase polymorphisms and isothiocyanate intake in the Singapore Chinese Health Study Carcinogenesis, December 1, 2006; 27(12): 2475 - 2482. [Abstract] [Full Text] [PDF]

				K. W. Rahman, F. H. Sarkar, S. Banerjee, Z. Wang, D. J. Liao, X. Hong, and N. H. Sarkar Therapeutic intervention of experimental breast cancer bone metastasis by indole-3-carbinol in SCID-human mouse model. Mol. Cancer Ther., November 1, 2006; 5(11): 2747 - 2756. [Abstract] [Full Text] [PDF]

				Z. Yu, B. Mahadevan, C. V. Lohr, K. A. Fischer, M. A. Louderback, S. K. Krueger, C. B. Pereira, D. J. Albershardt, W. M. Baird, G. S. Bailey, et al. Indole-3-carbinol in the maternal diet provides chemoprotection for the fetus against transplacental carcinogenesis by the polycyclic aromatic hydrocarbon dibenzo[a,l]pyrene Carcinogenesis, October 1, 2006; 27(10): 2116 - 2123. [Abstract] [Full Text] [PDF]

				Y. Takada, M. Andreeff, and B. B. Aggarwal Indole-3-carbinol suppresses NF-{kappa}B and I{kappa}B{alpha} kinase activation, causing inhibition of expression of NF-{kappa}B-regulated antiapoptotic and metastatic gene products and enhancement of apoptosis in myeloid and leukemia cells Blood, July 15, 2005; 106(2): 641 - 649. [Abstract] [Full Text] [PDF]

				G. Brandi, G. F. Schiavano, N. Zaffaroni, C. De Marco, M. Paiardini, B. Cervasi, and M. Magnani Mechanisms of Action and Antiproliferative Properties of Brassica oleracea Juice in Human Breast Cancer Cell Lines J. Nutr., June 1, 2005; 135(6): 1503 - 1509. [Abstract] [Full Text] [PDF]