Pentameric procyanidin from Theobroma cacao selectively inhibits growth of human breast cancer cells.
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.
Ramljak
Danica
D
Department of Oncology, The Research Building, Room W417, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Road, NW, Washington, District of Columbia 20057, USA.
Romanczyk
Leo J
LJ
Metheny-Barlow
Linda J
LJ
Thompson
Nicole
N
Knezevic
Vladimir
V
Galperin
Mikhail
M
Ramesh
Arun
A
Dickson
Robert B
RB
D000975:Antioxidants / Q000494:pharmacology; D001564:Benzo(a)pyrene / Q000494:pharmacology; D044946:Biflavonoids / Q000737:chemistry* / Q000627:therapeutic use*; D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms / Q000188:drug therapy*; D002392:Catechin / Q000737:chemistry* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D019660:Malvaceae / Q000378:metabolism*; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism; D010766:Phosphorylation; D010936:Plant Extracts / Q000378:metabolism* / Q000627:therapeutic use; D044945:Proanthocyanidins / Q000737:chemistry* / Q000627:therapeutic use*; D011960:Receptors, Estrogen / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000975:Antioxidants; D044946:Biflavonoids; D010936:Plant Extracts; D044945:Proanthocyanidins; D011960:Receptors, Estrogen; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D001564:Benzo(a)pyrene; D012694:Serine; C017674:procyanidin; D002392:Catechin