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Mechanisms of growth inhibition induced by methylene-substituted and ring-substituted dims in breast cancer cells

One in 8 women will be diagnosed with breast cancer in the United States and
estrogen receptor (ER) status largely influences the type and subsequent success of
treatment employed. Although ER-positive breast cancer can be treated with endocrine
therapy, the more invasive ER-negative breast cancer is non-responsive to this therapy
and cytotoxic agents are often utilized which are associated with many adverse side
effects. Consequently, there is a genuine need to develop more effective, less toxic
treatments for invasive breast cancer.
Indole-3-carbinol is a phytochemical found in cruciferous vegetables and one of
its major metabolites, 3,3’-diindolylmethane (DIM), exhibits a broad range of anticancer
and antitumorigenic activities. ER-negative MDA-MB-231 and MDA-MB-453 breast
cancer cell growth was inhibited after treatment with a novel series of methylenesubstituted
DIMs (C-DIMs), namely 1,1-bis(3’-indolyl)-1-(p-substitutedphenyl)
methanes containing trifluoromethyl (DIM-C-pPhCF3), t-butyl (DIM-C-pPhtBu) and
phenyl (DIM-C-pPhC6H5) groups. In addition, DIM-C-pPhC6H5 (40 mg/kg/d) inhibited
tumor growth in nude mice bearing MDA-MB-231 cells as xenografts. Treatment of breast cancer cells with C-DIMs lead to downregulation of cyclin D1 and induction of
non-steroidal anti-inflammatory drug-activated gene 1. Detection of necrosis, caspasedependent
or caspase-independent apoptosis were not observed in breast cancer cells
treated with C-DIMs, however autophagic cell death was induced by C-DIMs.
DIM and ring-substituted DIMs have exhibited antitumorigenic activity in tumor
murine mammary models. An investigation into the mechanism of cell death induced by
DIM and 5,5’-dibromoDIM (5,5’-diBrDIM) in both ER-positive (MCF-7) and ERnegative
(MDA-MB-231) breast cancer cells revealed modulation of several key
signaling pathways involved in growth control. Both DIM and 5,5’-diBrDIM
downregulated cyclin D1, although only 5,5’-diBrDIM induced a depolarization of the
mitochondrial membrane. In addition, apoptosis was observed in MCF-7 cells treated
with 5,5’-diBrDIM but not MDA-MB-231 cells.
In summary, C-DIMs may represent new mechanism-based agents for treatment
of breast cancer through induction of autophagic cell death. The ring-substituted DIMs
correspond to a novel class of uncharged mitochondrial poisons that are also highly
effective in inhibiting breast cancer cell growth. Results of this research provide
evidence for the potential role of two new series of DIM analogs for the treatment of
highly aggressive breast cancer.

Identiferoai:union.ndltd.org:tamu.edu/oai:repository.tamu.edu:1969.1/ETD-TAMU-1381
Date15 May 2009
CreatorsVanderlaag, Kathryn Elisabeth
ContributorsSafe, Stephen H.
Source SetsTexas A and M University
Languageen_US
Detected LanguageEnglish
TypeBook, Thesis, Electronic Dissertation, text
Formatelectronic, application/pdf, born digital

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