Pentameric procyanidin from Theobroma cacao selectively inhibits growth of human breast cancer cells

• Published in: Molecular cancer therapeutics Vol. 4; no. 4; pp. 537 - 546
• Main Authors: Ramljak, Danica, Romanczyk, Leo J, Metheny-Barlow, Linda J, Thompson, Nicole, Knezevic, Vladimir, Galperin, Mikhail, Ramesh, Arun, Dickson, Robert B
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.04.2005
• Subjects: Antioxidants - pharmacology; Benzo(a)pyrene - pharmacology; Biflavonoids - chemistry; Biflavonoids - therapeutic use; Breast - cytology; breast cancer; Breast Neoplasms - drug therapy; Catechin - chemistry; Catechin - therapeutic use; Cdc2; Cell Line, Tumor; Cell Proliferation - drug effects; cocoa procyanidins; Down-Regulation; Epithelial Cells - cytology; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunoblotting; Malvaceae - metabolism; Membrane Potentials; mitochondria; Mitochondria - metabolism; p53; Phosphorylation; Plant Extracts - metabolism; Plant Extracts - therapeutic use; Proanthocyanidins - chemistry; Proanthocyanidins - therapeutic use; Receptors, Estrogen - metabolism; Retinoblastoma Protein - metabolism; Serine - chemistry; Time Factors; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-04-0286

A naturally occurring, cocoa-derived pentameric procyanidin (pentamer) was previously shown to cause G 0 /G 1 cell cycle arrest in human breast cancer cells by an unknown molecular mechanism. Here, we show that pentamer selectively inhibits the proliferation of human breast cancer cells (MDA MB-231, MDA MB-436, MDA MB-468, SKBR-3, and MCF-7) and benzo( a )pyrene-immortalized 184A1N4 and 184B5 cells. In contrast, normal human mammary epithelial cells in primary culture and spontaneously immortalized MCF-10A cells were significantly resistant. We evaluated whether this differential response to pentamer may involve depolarization of the mitochondrial membrane. Pentamer caused significant depolarization of mitochondrial membrane in MDA MB231 cells but not the more normal MCF-10A cells, whereas other normal and tumor cell lines tested gave variable results. Further investigations, using a proteomics approach with pentamer-treated MDA MB-231, revealed a specific dephosphorylation, without changes in protein expression, of several G 1 -modulatory proteins: Cdc2 (at Tyr 15 ), forkhead transcription factor (at Ser 256 , the Akt phosphorylation site) and p53 (Ser 392 ). Dephosphorylation of p53 (at Ser 392 ) by pentamer was confirmed in MDA MB-468 cells. However, both expression and phosphorylation of retinoblastoma protein were decreased after pentamer treatment. Our results show that breast cancer cells are selectively susceptible to the cytotoxic effects of pentameric procyanidin, and suggest that inhibition of cellular proliferation by this compound is associated with the site-specific dephosphorylation or down-regulation of several cell cycle regulatory proteins.