title: Proanthocyanidin exposure to B6C3F1 mice significantly attenuates dimethylnitrosamine-induced liver tumor induction and mortality by differentially modulating programmed and unprogrammed cell deaths.
abstract: Proanthocyanidins are of current interest as chemopreventive agents. The potential of the pre-, post- and co-exposure of proanthocyanidin-rich grape seed extract (GSPE) in preventing, reducing and/or delaying dimethylnitrosamine (N-nitrosodimethylamine, DMN)-induced liver tumorigenesis, carcinogenesis and mortality in male B6C3F1 mice was determined. Animals were divided into six groups: I-control, II-GSPE alone, III-DMN alone, IV-GSPE+DMN, V-DMN exposure (3 months) followed by GSPE diet (9 months) and VI-GSPE diet (3 months)+DMN (3 months)+control diet (6 months). DMN exposure (0-8 weeks: 5mg/kg; 8-12 weeks: 10mg/kg, i.p.) was limited to a total period of 3 months. GSPE was incorporated in laboratory chow (ADI: 100mg/kg b.w.). Animals were sacrificed at 3 month intervals, and serum chemistry, liver histopathology, integrity of hepatic genomic DNA, antioxidant status, and rates of apoptotic and necrotic cell deaths were determined. DMN-induced liver tumor formation (85%) and animal lethality (38%) were powerfully antagonized by co-administration of GSPE+DMN (tumor positive: 45%; death: 11%). More than 75% of the DMN-treated animals had numerous tumors (five or more), which were significantly reduced in the GSPE+DMN group (35%). GSPE also negatively influenced other protocols specifically designed to test initiation and progression phases. Thus, GSPE was instrumental in modulating metabolic cascades and regulated orchestration of cell death processes involved during the multistage tumorigenic process. These results unraveled that long-term exposure to proanthocyanidin-rich grape seed extract may serve as a potent barrier to all three stages of DMN-induced liver carcinogenesis and tumorigenesis by selectively altering oxidative stress, genomic integrity and cell death patterns in vivo.
authors.affiliation: Division of Pharmaceutical Sciences, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY 11201, USA. sray@liu.edu
authors.forename: Sidhartha D
authors.initials: SD
authors.lastname: Ray
authors.forename: Hemal
authors.initials: H
authors.lastname: Parikh
authors.forename: Debasis
authors.initials: D
authors.lastname: Bagchi
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D003402:Creatine Kinase / Q000097:blood / Q000187:drug effects; D004128:Dimethylnitrosamine / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D044945:Proanthocyanidins / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000097:blood / Q000187:drug effects / Q000378:metabolism
chemical_list: D000975:Antioxidants; D008054:Lipid Peroxides; D010936:Plant Extracts; D044945:Proanthocyanidins; C013221:proanthocyanidin; D013482:Superoxide Dismutase; D003402:Creatine Kinase; D005978:Glutathione; D004128:Dimethylnitrosamine