PURPOSE: Fruit and vegetable intake is inversely correlated with cancer; thus, it is proposed that an extract of phytochemicals as present in whole fruits, vegetables, or grains may have anti-carcinogenic properties. Thus, the anti-tumour effects of fruit peel polyphenols (Flavin7) in the chemoprevention of N-methyl-N-nitrosourea-induced mammary carcinogenesis in female rats were evaluated. METHODS: Lyophilized substance of Flavin7 (F7) was administered at two concentrations of 0.3 and 3 % through diet. The experiment was terminated 14 weeks after carcinogen administration, and mammary tumours were removed and prepared for histopathological and immunohistochemical analysis. In addition, using an in vitro cytotoxicity assay, apoptosis and proliferation after F7 treatment in human breast adenocarcinoma (MCF-7) cells were performed. RESULTS: High-dose F7 suppressed tumour frequency by 58 % (P < 0.001), tumour incidence by 24 % (P < 0.05), and lengthened latency by 8 days (P > 0.05) in comparison with the control rats, whereas lower dose of F7 was less effective. Histopathological analysis of tumours showed significant decrease in the ratio of high-/low-grade carcinomas after high-dose F7 treatment. Immunohistochemical analysis of rat carcinoma cells in vivo found a significant increase in caspase-3 expression and significant decrease in Bcl-2, Ki67, and VEGFR-2 expression in the high-dose group. Both doses demonstrated significant positive effects on plasma lipid metabolism in rats. F7 significantly decreased survival of MCF-7 cells in vitro in MTT assay by dose- and time-dependent manner compared to control. F7 prevented cell cycle progression by significant enrichment in G1 cell populations. Incubation with F7 showed significant increase in the percentage of annexin V-/PI-positive MCF-7 cells and DNA fragmentation. CONCLUSIONS: Our results reveal a substantial tumour-suppressive effect of F7 in the breast cancer model. We propose that the effects of phytochemicals present in this fruit extract are responsible for observed potent anti-cancer activities.

Department of Anatomy Comenius University Martin Slovakia

Department of Animal Physiology Institute of Biological and Ecological Sciences Faculty of Science P J Šafárik University Moyzesova 11 040 01 Kosice Slovakia

Department of Biology and Ecology Faculty of Education Catholic University in Ružomberok Hrabovská cesta 1 034 01 Ružomberok Slovakia

Department of Histology and Embryology Comenius University Martin Slovakia

Department of Medical Biochemistry Comenius University Martin Slovakia

Department of Medical Biology Jessenius Faculty of Medicine Comenius University Malá Hora 4 036 01 Martin Slovakia

Department of Pathology St Elisabeth Oncology Institute Slovak Medical University Heydukova 10 812 50 Bratislava Slovakia

Department of Pharmacology Faculty of Medicine P J Šafárik University Tr SNP 1 040 01 Kosice Slovakia

International Clinical Research Center St Anne's University Hospital Masaryk University Pekarska 53 656 91 Brno Czech Republic

The Centre for Chronic Disease Prevention and Management Western CHRE Victoria University St Albans Australia

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$a Kubatka, Peter $u Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University, Malá Hora 4, 036 01, Martin, Slovakia. kubatka@jfmed.uniba.sk.

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$a Fruit peel polyphenols demonstrate substantial anti-tumour effects in the model of breast cancer / $c P. Kubatka, A. Kapinová, M. Kello, P. Kruzliak, K. Kajo, D. Výbohová, S. Mahmood, R. Murin, T. Viera, J. Mojžiš, A. Zulli, M. Péč, M. Adamkov, M. Kassayová, B. Bojková, N. Stollárová, D. Dobrota,

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$a PURPOSE: Fruit and vegetable intake is inversely correlated with cancer; thus, it is proposed that an extract of phytochemicals as present in whole fruits, vegetables, or grains may have anti-carcinogenic properties. Thus, the anti-tumour effects of fruit peel polyphenols (Flavin7) in the chemoprevention of N-methyl-N-nitrosourea-induced mammary carcinogenesis in female rats were evaluated. METHODS: Lyophilized substance of Flavin7 (F7) was administered at two concentrations of 0.3 and 3 % through diet. The experiment was terminated 14 weeks after carcinogen administration, and mammary tumours were removed and prepared for histopathological and immunohistochemical analysis. In addition, using an in vitro cytotoxicity assay, apoptosis and proliferation after F7 treatment in human breast adenocarcinoma (MCF-7) cells were performed. RESULTS: High-dose F7 suppressed tumour frequency by 58 % (P < 0.001), tumour incidence by 24 % (P < 0.05), and lengthened latency by 8 days (P > 0.05) in comparison with the control rats, whereas lower dose of F7 was less effective. Histopathological analysis of tumours showed significant decrease in the ratio of high-/low-grade carcinomas after high-dose F7 treatment. Immunohistochemical analysis of rat carcinoma cells in vivo found a significant increase in caspase-3 expression and significant decrease in Bcl-2, Ki67, and VEGFR-2 expression in the high-dose group. Both doses demonstrated significant positive effects on plasma lipid metabolism in rats. F7 significantly decreased survival of MCF-7 cells in vitro in MTT assay by dose- and time-dependent manner compared to control. F7 prevented cell cycle progression by significant enrichment in G1 cell populations. Incubation with F7 showed significant increase in the percentage of annexin V-/PI-positive MCF-7 cells and DNA fragmentation. CONCLUSIONS: Our results reveal a substantial tumour-suppressive effect of F7 in the breast cancer model. We propose that the effects of phytochemicals present in this fruit extract are responsible for observed potent anti-cancer activities.

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$a Kapinová, Andrea $u Department of Medical Biochemistry, Comenius University, Martin, Slovakia.

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$a Kello, Martin $u Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Tr. SNP 1, 040 01, Kosice, Slovakia.

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$a Kruzliak, Peter $u International Clinical Research Center, St. Anne's University Hospital, Masaryk University, Pekarska 53, 656 91, Brno, Czech Republic.

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$a Kajo, Karol $u Department of Pathology, St. Elisabeth Oncology Institute, Slovak Medical University, Heydukova 10, 812 50, Bratislava, Slovakia.

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$a Výbohová, Desanka $u Department of Anatomy, Comenius University, Martin, Slovakia.

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$a Mahmood, Silvia $u Department of Medical Biochemistry, Comenius University, Martin, Slovakia.

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$a Murin, Radovan $u Department of Medical Biochemistry, Comenius University, Martin, Slovakia.

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$a Viera, Tischlerová $u Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Tr. SNP 1, 040 01, Kosice, Slovakia.

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$a Mojžiš, Ján $u Department of Pharmacology, Faculty of Medicine, P. J. Šafárik University, Tr. SNP 1, 040 01, Kosice, Slovakia.

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$a Zulli, Anthony $u The Centre for Chronic Disease Prevention and Management (CCDPM), Western CHRE, Victoria University, St Albans, Australia.

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$a Péč, Martin $u Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University, Malá Hora 4, 036 01, Martin, Slovakia. pec@jfmed.uniba.sk.

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$a Adamkov, Marián $u Department of Histology and Embryology, Comenius University, Martin, Slovakia. $7 gn_A_00001422

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$a Kassayová, Monika $u Department of Animal Physiology, Institute of Biological and Ecological Sciences, Faculty of Science, P. J. Šafárik University, Moyzesova 11, 040 01, Kosice, Slovakia.

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$a Bojková, Bianka $u Department of Animal Physiology, Institute of Biological and Ecological Sciences, Faculty of Science, P. J. Šafárik University, Moyzesova 11, 040 01, Kosice, Slovakia.

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$a Stollárová, Nadežda $u Department of Biology and Ecology, Faculty of Education, Catholic University in Ružomberok, Hrabovská cesta 1, 034 01, Ružomberok, Slovakia.

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$a Dobrota, Dušan $u Department of Medical Biochemistry, Comenius University, Martin, Slovakia.

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