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 Ramljak, D. Articles by Dickson, R. B. Search for Related Content PubMed PubMed Citation Articles by Ramljak, D. Articles by Dickson, R. B.

¹ Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, District of Columbia; ² Masterfoods USA, Hackettstown, New Jersey; and ³ 20/20 Gene Systems, Rockville, Maryland

Requests for reprints: Robert B. Dickson, Department of Oncology, The Research Building, Room W417, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Road, NW, Washington, DC 20057. Phone: 202-687-3770; Fax: 202-687-7505. E-mail: dicksonr{at}georgetown.edu

A naturally occurring, cocoa-derived pentameric procyanidin (pentamer) was previously shown to cause G₀/G₁ 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 G₁-modulatory proteins: Cdc2 (at Tyr¹⁵), forkhead transcription factor (at Ser²⁵⁶, the Akt phosphorylation site) and p53 (Ser³⁹²). Dephosphorylation of p53 (at Ser³⁹²) 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.

Key Words: breast cancer • cocoa procyanidins • mitochondria • Cdc2 • p53

Grant support: Masterfoods USA.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 10/25/04; revised 2/ 4/05; accepted 2/21/05.

This article has been cited by other articles:

				T. Miura, M. Chiba, K. Kasai, H. Nozaka, T. Nakamura, T. Shoji, T. Kanda, Y. Ohtake, and T. Sato Apple procyanidins induce tumor cell apoptosis through mitochondrial pathway activation of caspase-3 Carcinogenesis, March 1, 2008; 29(3): 585 - 593. [Abstract] [Full Text] [PDF]