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      Bioinformatics and experimental studies of anti-leukemic activity from 6-gingerol demonstrate its role in p53 mediated apoptosis pathway

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          Abstract

          6-gingerol is a traditional medicine that possesses anti-cancer activity against several types of cancer. However, the mechanism of action still remains unclear. Therefore, this study explored the effects of 6-gingerol on anti-leukemic mechanisms in NB4, MOLT4, and Raji leukemic cell. Results indicated that 6-gingerol inhibited cell proliferation and induced cell apoptosis in these 3 cell lines. Moreover, 6-gingerol was shown to increase the mRNA expression of the caspase family thereby suggesting that 6-gingerol induced apoptosis through the caspase-dependent pathway. To explore the signaling pathway regulating 6-gingerol induced apoptosis, we utilized and integrated the network pharmacology approach together with experimental investigations. Targets of 6-gingerol were identified from ChEMBL and STITCH databases, which were used for constructing the protein-protein interaction (PPI) network. Results from the PPI network indicated that p53 was a key regulator. Moreover, it was found that 6-gingerol could increase the levels of p53 mRNA in all leukemic cell lines. Thus, 6-gingerol has shown to have anti-cancer activity. In addition, p53, BAX and BCL2 could be involved in the apoptosis pathway of these leukemic cells. This study is anticipated to be useful for the development of 6-gingerol as an anti-leukemic drug in the future.

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          Structure and evolution of transcriptional regulatory networks.

          M. Babu, Nicholas Luscombe, L Aravind … (2004)
          The regulatory interactions between transcription factors and their target genes can be conceptualised as a directed graph. At a global level, these regulatory networks display a scale-free topology, indicating the presence of regulatory hubs. At a local level, substructures such as motifs and modules can be discerned in these networks. Despite the general organisational similarity of networks across the phylogenetic spectrum, there are interesting qualitative differences among the network components, such as the transcription factors. Although the DNA-binding domains of the transcription factors encoded by a given organism are drawn from a small set of ancient conserved superfamilies, their relative abundance often shows dramatic variation among different phylogenetic groups. Large portions of these networks appear to have evolved through extensive duplication of transcription factors and targets, often with inheritance of regulatory interactions from the ancestral gene. Interactions are conserved to varying degrees among genomes. Insights from the structure and evolution of these networks can be translated into predictions and used for engineering of the regulatory networks of different organisms.
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            Chemopreventive effects of dietary phytochemicals against cancer invasion and metastasis: phenolic acids, monophenol, polyphenol, and their derivatives.

            Jui-Yun Weng, Chin-En Yen (2012)
            Cancer metastasis is the major cause of cancer-related death, and chemoprevention is defined as the use of natural or synthetic substances to prevent cancer formation or cancer progress. Evidence that phenolic compounds may have a potential inhibitory effect on cancer invasion and metastasis is increasingly being reported in the scientific literature. Curcumin, resveratrol, and their related derivatives are the most studied compounds in this topic so far; gallic acid, chlorogenic acid, caffeic acid, carnosol, capsaicin, 6-shogaol, 6-gingerol, and their corresponding derivatives are also suggested to be the active members of the phenolic family on anti-invasion and anti-metastasis. Because metastasis occurs through a multistep process, these bioactives might act on a variety of stages of the metastatic process to prevent tumor cells from metastasizing. This review summarizes the common protein targets and signaling pathways for the inhibition of invasion and metastasis as well as past publications on the in vitro and in vivo effects and molecular mechanisms of phenolic acids, monophenol, polyphenol, and their derivatives, except flavonoids, on cancer invasion and metastasis. Based on these data, we conclude that the daily consumption of natural dietary components that are rich in phenolics could be beneficial for the prevention of cancer metastasis. 2011 Elsevier Ltd. All rights reserved.
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              [6]-Gingerol inhibits metastasis of MDA-MB-231 human breast cancer cells.

              Hyun Lee, Eun Seo, Nam Kang … (2008)
              Gingerol (Zingiber officinale Roscoe, Zingiberaceae) is one of the most frequently and heavily consumed dietary condiments throughout the world. The oleoresin from rhizomes of ginger contains [6]-gingerol (1-[4'-hydroxy-3'-methoxyphenyl]-5-hydroxy-3-decanone) and its homologs which are pungent ingredients that have been found to possess many interesting pharmacological and physiological activities, such as anti-inflammatory, antihepatotoxic and cardiotonic effects. However, the effects of [6]-gingerol on metastatic processes in breast cancer cells are not currently well known. Therefore, in this study, we examined the effects of [6]-gingerol on adhesion, invasion, motility, activity and the amount of MMP-2 or -9 in the MDA-MB-231 human breast cancer cell line. We cultured MDA-MB-231 cells in the presence of various concentrations of [6]-gingerol (0, 2.5, 5 and 10 microM). [6]-Gingerol had no effect on cell adhesion up to 5 microM, but resulted in a 16% reduction at 10 microM. Treatment of MDA-MB-231 cells with increasing concentrations of [6]-gingerol led to a concentration-dependent decrease in cell migration and motility. The activities of MMP-2 or MMP-9 in MDA-MB-231 cells were decreased by treatment with [6]-gingerol and occurred in a dose-dependent manner. The amount of MMP-2 protein was decreased in a dose-dependent manner, although there was no change in the MMP-9 protein levels following treatment with [6]-gingerol. MMP-2 and MMP-9 mRNA expression were decreased by [6]-gingerol treatment. In conclusion, we have shown that [6]-gingerol inhibits cell adhesion, invasion, motility and activities of MMP-2 and MMP-9 in MDA-MB-231 human breast cancer cell lines.
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                Author and article information

                Journal
                Journal ID (nlm-ta): EXCLI J
                Journal ID (iso-abbrev): EXCLI J
                Journal ID (publisher-id): EXCLI J
                Title: EXCLI Journal
                Publisher: Leibniz Research Centre for Working Environment and Human Factors
                ISSN (Electronic): 1611-2156
                Publication date (Electronic): 06 May 2020
                Publication date Collection: 2020
                Volume: 19
                Pages: 582-595
                Affiliations
                [1 ]Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Nakhon Pathom 73170, Thailand
                [2 ]Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand
                [3 ]Proteomics Research Laboratory, National Center for Genetic Engineering and Biotechnology, 113 Thailand Science Park, Klongluang, Pathumthani 12120, Thailand
                [4 ]Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand
                Author notes
                *To whom correspondence should be addressed: Dalina Tanyong, Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Nakhon Pathom 73170, Thailand; Tel.: +668-1498-7611, E-mail: Dalina.itc@ 123456mahidol.ac.th
                Article
                Publisher ID: 2019-2008 Publisher ID: Doc582
                DOI: 10.17179/excli2019-2008
                PMC ID: 7257249
                PubMed ID: 32483405
                SO-VID: d016b1b1-c07e-4e7f-b6b2-3c6f5cb44070
                Copyright © Copyright © 2020 Chatupheeraphat et al.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence ( http://creativecommons.org/licenses/by/4.0/) You are free to copy, distribute and transmit the work, provided the original author and source are credited.

                History
                Date received : 26 November 2019
                Date accepted : 04 May 2020
                Categories
                Subject: Original Article

                Keywords: 6-gingerol,leukemia,apoptosis,network pharmacology,p53,bioinformatics
                Data availability:
                Keywords: 6-gingerol, leukemia, apoptosis, network pharmacology, p53, bioinformatics

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