Naturally-occurring mixtures of phytochemicals present in plant foods are proposed to possess tumor-suppressive activities. In this work, we aimed to evaluate the antitumor effects of Thymus vulgaris L. in in vivo and in vitro mammary carcinoma models. Dried T. vulgaris (as haulm) was continuously administered at two concentrations of 0.1% and 1% in the diet in a chemically-induced rat mammary carcinomas model and a syngeneic 4T1 mouse model. After autopsy, histopathological and molecular analyses of rodent mammary carcinomas were performed. In addition, in vitro evaluations using MCF-7 and MDA-MB-231 cells were carried out. In mice, T. vulgaris at both doses reduced the volume of 4T1 tumors by 85% (0.1%) and 84% (1%) compared to the control, respectively. Moreover, treated tumors showed a substantial decrease in necrosis/tumor area ratio and mitotic activity index. In the rat model, T. vulgaris (1%) decreased the tumor frequency by 53% compared to the control. Analysis of the mechanisms of anticancer action included well-described and validated diagnostic and prognostic markers that are used in both clinical approach and preclinical research. In this regard, the analyses of treated rat carcinoma cells showed a CD44 and ALDH1A1 expression decrease and Bax expression increase. Malondialdehyde (MDA) levels and VEGFR-2 expression were decreased in rat carcinomas in both the T. vulgaris treated groups. Regarding the evaluations of epigenetic changes in rat tumors, we found a decrease in the lysine methylation status of H3K4me3 in both treated groups (H3K9m3, H4K20m3, and H4K16ac were not changed); up-regulations of miR22, miR34a, and miR210 expressions (only at higher doses); and significant reductions in the methylation status of four gene promoters-ATM serin/threonine kinase, also known as the NPAT gene (ATM); Ras-association domain family 1, isoform A (RASSF1); phosphatase and tensin homolog (PTEN); and tissue inhibitor of metalloproteinase-3 (TIMP3) (the paired-like homeodomain transcription factor (PITX2) promoter was not changed). In vitro study revealed the antiproliferative and proapoptotic effects of essential oils of T. vulgaris in MCF-7 and MDA-MB-231 cells (analyses of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS); 5-bromo-20-deoxyuridine (BrdU); cell cycle; annexin V/PI; caspase-3/7; Bcl-2; PARP; and mitochondrial membrane potential). T. vulgaris L. demonstrated significant chemopreventive and therapeutic activities against experimental breast carcinoma.

Biomedical Research Center Slovak Academy of Sciences 845 05 Bratislava Slovakia

Department of Anatomy Jessenius Faculty of Medicine Comenius University in Bratislava 036 01Martin Slovakia

Department of Animal Physiology Institute of Biology and Ecology Faculty of Science P J Šafarik University 040 01 Košice Slovakia

Department of Histology and Embryology Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Department of Immunology and School of Medicine Keimyung University Dalseo Gu Daegu 426 01 Korea

Department of Medical Biology Faculty of Medicine P J Safarik University Kosice 040 11 Slovakia

Department of Medical Biology Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Department of Natural Drugs Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences 612 42 Brno Czech Republic

Department of Obstetrics and Gynecology Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Department of Pharmacology Faculty of Medicine P J Šafarik University 040 11 Košice Slovakia

Division of Oncology Biomedical Center Martin Jessenius Faculty of Medicine Comenius University in Bratislava 036 01 Martin Slovakia

Institute for Health and Sport Victoria University Melbourne VIC 3011 Australia

St Elisabeth Oncology Institute Department of Pathology 812 50 Bratislava Slovakia

Weill Cornell Medicine in Qatar Qatar Foundation Education City Doha 24144 Qatar

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