Abstract
BackgroundPlants have proved to be an important source of anti-cancer drugs. Here we have investigated the cytotoxic action of an aqueous extract of Fagonia cretica, used widely as a herbal tea-based treatment for breast cancer.Methodology/Principal FindingsUsing flow cytometric analysis of cells labeled with cyclin A, annexin V and propidium iodide, we describe a time and dose-dependent arrest of the cell cycle in G0/G1 phase of the cell cycle and apoptosis following extract treatment in MCF-7 (WT-p53) and MDA-MB-231 (mutant-p53) human breast cancer cell lines with a markedly reduced effect on primary human mammary epithelial cells. Analysis of p53 protein expression and of its downstream transcription targets, p21 and BAX, revealed a p53 associated growth arrest within 5 hours of extract treatment and apoptosis within 24 hours. DNA double strand breaks measured as γ-H2AX were detected early in both MCF-7 and MDA-MB-231 cells. However, loss of cell viability was only partly due to a p53-driven response; as MDA-MB-231 and p53-knockdown MCF-7 cells both underwent cell cycle arrest and death following extract treatment. p53-independent growth arrest and cytotoxicity following DNA damage has been previously ascribed to FOXO3a expression. Here, in MCF-7 and MDA-MB-231 cells, FOXO3a expression was increased significantly within 3 hours of extract treatment and FOXO3 siRNA reduced the extract-induced loss of cell viability in both cell lines.Conclusions/SignificanceOur results demonstrate for the first time that an aqueous extract of Fagonia cretica can induce cell cycle arrest and apoptosis via p53-dependent and independent mechanisms, with activation of the DNA damage response. We also show that FOXO3a is required for activity in the absence of p53. Our findings indicate that Fagonia cretica aqueous extract contains potential anti-cancer agents acting either singly or in combination against breast cancer cell proliferation via DNA damage-induced FOXO3a and p53 expression.
Highlights
Following genotoxic stress, an intact DNA damage response (DDR) is necessary to eliminate lethal and tumorigenic mutations
Conclusions/Significance: Our results demonstrate for the first time that an aqueous extract of Fagonia cretica can induce cell cycle arrest and apoptosis via p53-dependent and independent mechanisms, with activation of the DNA damage response
In order to determine whether an aqueous extract of Fagonia cretica had any cytotoxicity towards normal and breast cancer cells in vitro, we tested its effects on MCF-7 and MDA-MB-231 cell viability and cell cycle status, alongside HMEpC
Summary
An intact DNA damage response (DDR) is necessary to eliminate lethal and tumorigenic mutations. An impairment in the DNA damage response represents a doubleedged sword, where on one side loss of repair mechanisms can drive tumorigenesis and on the other, can affect sensitivity to genotoxic chemotherapy [2,3]. In response to stress signals, post-translational modifications of p53 such as phosphorylation, drive its nuclear translocation and subsequent target gene transcription [6,7]. Dissociation of the MDM2p53 repressor complex, prevents monoubiquitination of p53 and its degradation [9,10]. This in turn increases p53 half-life and activates its transcriptional program [11]. We have investigated the cytotoxic action of an aqueous extract of Fagonia cretica, used widely as a herbal tea-based treatment for breast cancer
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