title: Effect of annatto-tocotrienols supplementation on the development of mammary tumors in HER-2/neu transgenic mice.
abstract: Tocotrienols (T3), the lesser known isomers of vitamin E, have been reported to possess anticancer activity both in in vitro and in vivo experimental models of rodents transplanted with parental tumors or treated with carcinogens. We investigated the effects of dietary supplementation with annatto-T3 (90% δ-T3 and 10% γ-T3) on the spontaneous development of mammary tumors in HER-2/neu transgenic mice. Underlying mechanisms of the antitumor effect were evaluated by studying apoptosis, senescent-like growth arrest, immune modulation, oxidative effect and the expression of HER-2/neu in tumoral mammary glands of transgenic mice and in vitro in human and mice tumor cell lines. Annatto-T3 supplementation delayed the development of mammary tumors, reducing the number and size of mammary tumor masses and those of lung metastases. In annatto-T3-supplemented mice, both apoptosis and senescent-like growth arrest of tumor cells were increased in mammary glands while no immune modulation was observed. In vitro, a dose-dependent inhibition of cell growth, increased apoptosis and senescent-like growth arrest and a time-dependent accumulation of reactive oxygen species were observed in tumor cells treated with annatto-T3 or purified δ-T3. Annatto-T3 reduced both HER-2/neu mRNA and p185(HER-2/neu) protein in tumors and in tumor cell lines. The results show that the antitumor effect of annatto-T3 supplementation in HER-2/neu transgenic mice is mainly related to the direct induction of oxidative stress, senescent-like growth arrest and apoptosis of tumor cells rather than to an immune modulation.
authors: Advanced Technology Center for Aging Research, Scientific Technological Area, IRCCS-INRCA, Via Birarelli 8, 60121 Ancona, Italy.
authors: Elisa
authors: E
authors: Pierpaoli
authors: Valentina
authors: V
authors: Viola
authors: Alessandra
authors: A
authors: Barucca
authors: Fiorenza
authors: F
authors: Orlando
authors: Francesco
authors: F
authors: Galli
authors: Mauro
authors: M
authors: Provinciali
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000517:prevention & control*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D031212:Bixaceae; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000517:prevention & control*; D002338:Carotenoids / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D018890:Chemoprevention; D019587:Dietary Supplements; D005260:Female; D005505:Food Coloring Agents / Q000008:administration & dosage / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000187:drug effects; D010936:Plant Extracts / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics*; D014018:Tissue Distribution; D024508:Tocotrienols / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D002338:Carotenoids; D005505:Food Coloring Agents; D010936:Plant Extracts; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018719:Erb-b2 Receptor Tyrosine Kinases; D024508:Tocotrienols; C054041:annatto; C524056:Erbb2 protein, mouse