1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit proliferation of estrogen receptor-negative breast cancer cells by activation of multiple pathways.
1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing para-trifluoromethyl (DIM-C-pPhCF(3)), t-butyl (DIM-C-pPhtBu), and phenyl (DIM-C-pPhC(6)H(5)) groups are methylene-substituted diindolylmetyhanes (C-DIMs) that activate peroxisome proliferator-activated receptor gamma (PPARgamma) in estrogen receptor alpha-negative MDA-MB-231 and MDA-MB-453 breast cancer cells. C-DIMs inhibit breast cancer cell proliferation; however, inhibition of G(0)/G(1) to S phase progression and cyclin D1 downregulation was observed in MDA-MB-231 but not MDA-MB-453 cells. Nonsteroidal anti-inflammatory drug-activated gene 1 (NAG-1), a transforming growth factor beta-like peptide, was also induced by these compounds, and the response was dependent on cell-context dependent activation of kinase pathways. However, inhibition of cell growth, induction of NAG-1 and activation of kinases by C-DIMs were not inhibited by PPARgamma antagonists. Despite the induction of NAG-1 and downregulation of the antiapoptotic protein survivin by C-DIMs in both MDA-MB-231 and MDA-MB-453 cells, apoptotic cell death was not observed. Nevertheless, the cytotoxicity of C-DIMs in vitro was complemented by inhibition of tumor growth in athymic nude mice bearing MDA-MB-231 cells as xenografts and treated with DIM-C-pPhC(6)H(5) (40 mg/kg/day). The growth inhibition of tumors derived from highly aggressive MDA-MB-231 cells suggests a potential role for the C-DIM compounds in the clinical treatment of ER-negative breast cancer.
Vanderlaag
Kathy
K
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA.
Su
Yunpeng
Y
Frankel
Arthur E
AE
Grage
Henry
H
Smith
Roger
R
Khan
Shaheen
S
Safe
Stephen
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D055436:Growth Differentiation Factor 15; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D047495:PPAR gamma / Q000037:antagonists & inhibitors; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
C505816:1,1-bis(3'-indolyl)-1-(4-t-butylphenyl)methane; D000970:Antineoplastic Agents; D016207:Cytokines; C526140:GDF15 protein, human; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; D007211:Indoles; D047495:PPAR gamma; D011960:Receptors, Estrogen; D011494:Protein Kinases