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      Flavokawain derivative FLS induced G2/M arrest and apoptosis on breast cancer MCF-7 cell line

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          Known as naturally occurring biologically active compounds, flavokawain A and B are the leading chalcones that possess anticancer properties. Another flavokawain derivative, (E)-1-(2′-Hydroxy-4′,6′-dimethoxyphenyl)-3-(4-methylthio)phenyl)prop-2-ene-1-one (FLS) was characterized with 1H-nuclear magnetic resonance, electron-impact mas spectrometry, infrared spectroscopy, and ultraviolet ( 1H NMR, EI-MS, IR, and UV) spectroscopic techniques. FLS cytotoxic efficacy against human cancer cells (MCF-7, MDA-MB-231, and MCF-10A) resulted in the reduction of IC 50 values in a time- and dose-dependent mode with high specificity on MCF-7 (IC 50 of 36 μM at 48 hours) against normal breast cell MCF-10A (no IC 50 detected up to 180 μM at 72 hours). Light, scanning electron, and fluorescent microscopic analysis of MCF-7 cells treated with 36 μM of FLS displayed cell shrinkage, apoptotic body, and DNA fragmentation. Additionally, induction of G2/M cell arrest within 24 hours and apoptosis at subsequent time points was discovered via flow cytometry analysis. The roles of PLK-1, Wee-1, and phosphorylation of CDC-2 in G2/M arrest and proapoptotic factors (Bax, caspase 9, and p53) in promotion of apoptosis of FLS against MCF-7 cells were discovered using fluorometric, quantitative real-time polymerase chain reaction, and Western blot analysis. Interestingly, the presence of SCH 3 (thiomethyl group) on ring B structure contributed to the selective cytotoxicity against MCF-7 cells compared to other chalcones, flavokawain A and B. Overall, our data suggest potential therapeutic value for flavokawain derivative FLS to be further developed as a new anticancer drug.

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          Most cited references 17

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          Cytochrome C-mediated apoptosis.

          Apoptosis, or programmed cell death, is involved in development, elimination of damaged cells, and maintenance of cell homeostasis. Deregulation of apoptosis may cause diseases, such as cancers, immune diseases, and neurodegenerative disorders. Apoptosis is executed by a subfamily of cysteine proteases known as caspases. In mammalian cells, a major caspase activation pathway is the cytochrome c-initiated pathway. In this pathway, a variety of apoptotic stimuli cause cytochrome c release from mitochondria, which in turn induces a series of biochemical reactions that result in caspase activation and subsequent cell death. In this review, we focus on the recent progress in understanding the biochemical mechanisms and regulation of the pathway, the roles of the pathway in physiology and disease, and their potential therapeutic values.
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            Trends in utilization of the pharmacological potential of chalcones.

            Chalcones (1,3-diaryl-2-propen-1-ones) are open chain flavonoids that are widely biosynthesized in plants. They are important for the pigmentation of flowers and, hence, act as attractants to the pollinators. As flavonoids, chalcones also play an important role in defense against pathogens and insects. A longstanding scientific research has shown that chalcones also display other interesting biological properties such as antioxidant, cytotoxic, anticancer, antimicrobial, antiprotozoal, antiulcer, antihistaminic and anti-inflammatory activities. Some lead compounds with various pharmacological properties have been developed based on the chalcone skeleton. Clinical trials have shown that these compounds reached reasonable plasma concentrations and did not cause toxicity. For these reasons, chalcones became an object of continued interest in both academia and industry. Nowadays, several chalcones are used for treatment of viral disorders, cardiovascular diseases, parasitic infections, pain, gastritis, and stomach cancer, as well as like food additives and cosmetic formulation ingredients. However, much of the pharmacological potential of chalcones is still not utilized. The purpose of this review is to describe the recent efforts of scientists in pharmacological screening of natural and synthetic chalcones, studying the mechanisms of chalcone action and relevant structure-activity relationships. Put together, these activities aimed at synthesis of pharmacologically active chalcones and their analogs.
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              Flavokawain B, a novel chalcone from Alpinia pricei Hayata with potent apoptotic activity: Involvement of ROS and GADD153 upstream of mitochondria-dependent apoptosis in HCT116 cells.

              Flavonoids synthesized from chalcone precursors in plants have been shown to possess cytotoxic activities with therapeutic potential. We have isolated the novel chalcone flavokawain B from Alpinia pricei Hayata, a plant native to Taiwan that is used in food and traditional Chinese medicine. Here, we report for the first time that flavokawain B significantly inhibits the growth of colon cancer cells and provide novel insight into the molecular mechanisms that underlie its apoptotic activity. Flavokawain B exerts its apoptotic action through ROS generation and GADD153 up-regulation, which lead to mitochondria-dependent apoptosis characterized by release of cytochrome c and translocation of Bak. The up-regulation of GADD153 in flavokawain B-treated HCT116 cells is associated with mitochondrial dysfunction and altered expression of Bcl-2 family members. Moreover, pretreatment with the ROS scavenger N-acetylcysteine abolishes flavokawain B-induced ROS generation, GADD153 up-regulation, and apoptosis. Similarly, RNAi-mediated gene silencing reduced flavokawain B-enhanced expression of GADD153 and apoptotic Bim, leading to diminished apoptosis. Interestingly, flavokawain B provokes G2/M accumulation as well as autophagy, in addition to apoptosis, suggesting that multiple pathways are activated in flavokawain B-mediated anticancer activity. Taken together, our data provide evidence for a molecular mechanism to explain the apoptotic activity of Alpinia plants, showing that flavokawain B acts through ROS generation and GADD153 up-regulation to regulate the expression of Bcl-2 family members, thereby inducing mitochondrial dysfunction and apoptosis in HCT116 cells. Copyright 2010 Elsevier Inc. All rights reserved.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                10 June 2016
                : 10
                : 1897-1907
                [1 ]Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Selangor, Malaysia
                [2 ]Department of Industrial Biotechnology, Faculty of Industrial Sciences & Technology, Universiti Malaysia Pahang, Pahang, Malaysia
                [3 ]Department of Agriculture Genetics and Breeding, College of Agriculture and Applied Biology, Cantho University, CanTho City, Vietnam
                [4 ]Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Selangor, Malaysia
                [5 ]School of Biomedical Sciences, The University of Nottingham Malaysia Campus, Selangor, Malaysia
                [6 ]Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia
                [7 ]Tissue Engineering Group, National Orthopaedic Centre of Excellence for Research and Learning, Department of Orthopaedic Surgery, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
                Author notes
                Correspondence: Swee Keong Yeap, Institute of Bioscience, Lebuh Silicon, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia, Tel +60 3 894 72153, Fax +60 3 894 72153, Email skyeap2005@ 123456gmail.com
                © 2016 Ali et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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