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      Tanacetum polycephalum (L.) Schultz-Bip. Induces Mitochondrial-Mediated Apoptosis and Inhibits Migration and Invasion in MCF7 Cells

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          Abstract

          Tanacetum polycephalum (L.) Schultz-Bip (Mokhaleseh) has been traditionally used in the treatment of headaches, migraines, hyperlipidemia and diabetes. The present study aimed to evaluate its anticancer properties and possible mechanism of action using MCF7 as an in vitro model. T. polycephalum leaves were extracted using hexane, chloroform and methanol solvents and the cytotoxicity was evaluated using the MTT assay. Detection of the early apoptotic cells was investigated using acridine orange/propidium iodide staining. An Annexin-V-FITC assay was carried out to observe the phosphatidylserine externalization as a marker for apoptotic cells. High content screening was applied to analyze the cell membrane permeability, nuclear condensation, mitochondrial membrane potential (MMP) and cytochrome c release. Apoptosis was confirmed by using caspase-8, caspase-9 and DNA laddering assays. In addition, Bax/Bcl-2 expressions and cell cycle arrest also have been investigated. MTT assay revealed significant cytotoxicity of T. Polycephalum hexane extract (TPHE) on MCF7 cells with the IC 50 value of 6.42 ± 0.35 µg/mL. Significant increase in chromatin condensation was also observed via fluorescence analysis. Treatment of MCF7 cells with TPHE encouraged apoptosis through reduction of MMP by down-regulation of Bcl-2 and up-regulation of Bax, triggering the cytochrome c leakage from mitochondria to the cytosol. The treated MCF7 cells significantly arrested at G 1 phase. The chromatographic analysis elicited that the major active compound in this extract is 8β-hydroxy-4β,15-dihydrozaluzanin C. Taken together, the results presented in this study demonstrated that the hexane extract of T. Polycephalum inhibits the proliferation of MCF7 cells, resulting in the cell cycle arrest and apoptosis, which was explained to be through the mitochondrial pathway.

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          Most cited references 44

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          Mechanisms of cytochrome c release from mitochondria.

          In healthy cells, cytochrome c (Cyt c) is located in the mitochondrial intermembrane/intercristae spaces, where it functions as an electron shuttle in the respiratory chain and interacts with cardiolipin (CL). Several proapoptotic stimuli induce the permeabilization of the outer membrane, facilitate the communication between intermembrane and intercristae spaces and promote the mobilization of Cyt c from CL, allowing for Cyt c release. In the cytosol, Cyt c mediates the allosteric activation of apoptosis-protease activating factor 1, which is required for the proteolytic maturation of caspase-9 and caspase-3. Activated caspases ultimately lead to apoptotic cell dismantling. Nevertheless, cytosolic Cyt c has been associated also to vital cell functions (i.e. differentiation), suggesting that its release not always occurs in an all-or-nothing fashion and that mitochondrial outer membrane permeabilization may not invariably lead to cell death. This review deals with the events involved in Cyt c release from mitochondria, with special attention to its regulation and final consequences.
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            What made sesquiterpene lactones reach cancer clinical trials?

            Sesquiterpene lactones (SLs) are plant-derived compounds often used in traditional medicine against inflammation and cancer. This review focuses on the chemical and biological properties of SLs that lead to enhanced anticancer and anti-inflammatory effects. The chemical properties comprise alkylating center reactivity, lipophilicity, and molecular geometry and electronic features. SLs in clinical trials are artemisinin, thapsigargin and parthenolide and many of their synthetic derivatives. These drugs are selective toward tumor and cancer stem cells by targeting specific signaling pathways, which make them lead compounds in cancer clinical trials.
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              Targeting the extrinsic apoptosis pathway in cancer.

               Avi Ashkenazi (2015)
              Mutational inactivation of the p53 tumor-suppressor gene, which regulates apoptosis mainly via the cell-intrinsic pathway, reduces the sensitivity of many cancers to conventional treatments. Targeting the cell-extrinsic pathway, which triggers p53-independent apoptosis, offers a unique therapeutic strategy to induce apoptosis in cancer cells. This article focuses on two proapoptotic receptor agonists, recombinant human Apo2-ligand/TNF-related apoptosis-inducing ligand (rhApo2L/TRAIL) and Apomab, which activate death receptor (DR) 4 and/or DR5, thus stimulating the cell-extrinsic pathway. These agents are under investigation for the treatment of solid tumor and hematologic malignancies. Preclinical data indicate that both molecules cause significant regression or growth inhibition of malignant tumors without significant toxicity. Initial data on rhApo2L/TRAIL and Apomab from phase 1 safety trials also confirm that these agents are suitable for further clinical investigation.
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                Author and article information

                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                03 July 2014
                July 2014
                : 19
                : 7
                : 9478-9501
                Affiliations
                [1 ]Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia; E-Mails: mahbobehrazavi@ 123456gmail.com (M.R.); aditya@ 123456um.edu.my (A.A.); behnam@ 123456um.edu.my (B.K.); ibrahimn@ 123456um.edu.my (M.I.N.)
                [2 ]Medical Research Centre, Jazan University, Jazan 2092, Saudi Arabia; E-Mails: syammohanm@ 123456yahoo.com (S.M.); hapipah@ 123456um.edu.my (H.M.A.)
                [3 ]Biomolecular Research Group, Biochemistry Program, Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia; E-Mail: soheil.zorofchian@ 123456gmail.com
                [4 ]Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur 50603, Malaysia; E-Mail: mehranfadaie_n@ 123456yahoo.com
                Author notes
                [* ]Author to whom correspondence should be addressed; E-Mail: hamed_karimian61@ 123456yahoo.com ; Tel.: +60-3-796-778-08; Fax: +60-3-796-778-13.
                Article
                molecules-19-09478
                10.3390/molecules19079478
                6270824
                24995928
                © 2014 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/4.0/).

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