title: Diosmin-induced senescence, apoptosis and autophagy in breast cancer cells of different p53 status and ERK activity.
abstract: Relatively low bioavailability of plant-derived nutraceuticals with anticancer properties may limit their usefulness for prevention and therapy of cancer. In the present study, we have screened for nutraceuticals (n=30) that would act at low micromolar range against phenotypically distinct breast cancer cell lines, namely MCF-7 (ER+, PR+/-, HER2-), MDA-MB-231 (ER-, PR-, HER2-) and SK-BR-3 (ER-, PR-, HER2+), and diosmin, a citrus fruit flavonoid belonging to a flavone subclass, was selected. MCF-7 cell line was found to be the most sensitive to diosmin treatment. Diosmin caused G2/M cell cycle arrest, elevation in p53, p21 and p27 levels and stress-induced premature senescence when used at lower concentrations (5 and 10μM). Diosmin (20μM) also promoted apoptosis that was not observed in normal human mammary epithelial cells (HMEC). Diosmin stimulated oxidative and nitrosative stress, DNA damage and changes in global DNA methylation patterns. The status of p53 (wild type versus mutant) and the levels of phosphorylated ERK1/2 in a steady state, and diosmin-induced autophagy may reflect diverse response to diosmin treatment in MCF-7, MDA-MB-231 and SK-BR-3 cells, which in turn results in different cell fates. Taken together, diosmin that acts at low micromolar range against breast cancer cells may be considered as a promising candidate for anticancer therapy.
authors.affiliation: Department of Genetics, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland. Electronic address: alewinska@o2.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Lewinska
authors.affiliation: Department of Genetics, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland.
authors.forename: Jagoda
authors.initials: J
authors.lastname: Adamczyk-Grochala
authors.affiliation: Department of Genetics, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Kwasniewicz
authors.affiliation: Department of Genetics, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Deregowska
authors.affiliation: Department of Genetics, University of Rzeszow, Werynia 502, 36-100 Kolbuszowa, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Wnuk
mesh_terms: D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D004145:Diosmin / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D061986:MCF-7 Cells; D018384:Oxidative Stress / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016588:Anticarcinogenic Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004145:Diosmin
keywords: Apoptosis; Autophagy; Breast cancer cells; Diosmin; ERK activity; Senescence