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Open AccessArticle

Anticancer Activities of Thymus vulgaris L. in Experimental Breast Carcinoma In Vivo and In Vitro

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Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
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Division of Oncology, Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
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Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
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Department of Pharmacology, Faculty of Medicine, P. J. Šafarik University, 040 11 Košice, Slovakia
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St. Elisabeth Oncology Institute, Department of Pathology, 812 50 Bratislava, Slovakia
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Biomedical Research Center, Slovak Academy of Sciences, 845 05 Bratislava, Slovakia
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Department of Anatomy, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia
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Department of Histology and Embryology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia, [email protected]
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Department of Natural Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, 612 42 Brno, Czech Republic
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Department of Medical Biology, Faculty of Medicine, P. J. Safarik University, 040 11 Kosice, Slovakia
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Weill Cornell Medicine in Qatar, Qatar Foundation-Education City, Doha 24144, Qatar
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Institute for Health and Sport, Victoria University, Melbourne, VIC 3011, Australia
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Department of Animal Physiology, Institute of Biology and Ecology, Faculty of Science, P. J. Šafarik University, 040 01 Košice, Slovakia
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Department of Immunology and School of Medicine, Keimyung University, Dalseo-Gu, Daegu 426 01, Korea
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(7), 1749; https://doi.org/10.3390/ijms20071749
Received: 26 February 2019 / Revised: 2 April 2019 / Accepted: 6 April 2019 / Published: 9 April 2019
(This article belongs to the Special Issue The Effect of Dietary Factors on Cancer)
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. View Full-Text
Keywords: angiogenesis; apoptosis; cancer stem cells; cell proliferation; epigenetics; mammary carcinogenesis; MCF-7 cells; MDA-MB-231 cells; predictive and preventive medicine; rat; Thymus vulgaris angiogenesis; apoptosis; cancer stem cells; cell proliferation; epigenetics; mammary carcinogenesis; MCF-7 cells; MDA-MB-231 cells; predictive and preventive medicine; rat; Thymus vulgaris
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Kubatka, P.; Uramova, S.; Kello, M.; Kajo, K.; Samec, M.; Jasek, K.; Vybohova, D.; Liskova, A.; Mojzis, J.; Adamkov, M.; Zubor, P.; Smejkal, K.; Svajdlenka, E.; Solar, P.; Samuel, S.M.; Zulli, A.; Kassayova, M.; Lasabova, Z.; Kwon, T.K.; Pec, M.; Danko, J.; Büsselberg, D. Anticancer Activities of Thymus vulgaris L. in Experimental Breast Carcinoma In Vivo and In Vitro. Int. J. Mol. Sci. 2019, 20, 1749.

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