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      Mapping Pharmacological Network of Multi-Targeting Litchi Ingredients in Cancer Therapeutics

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          Abstract

          Considerable pharmacological studies have demonstrated that the extracts and ingredients from different parts (seeds, peels, pulps, and flowers) of Litchi exhibited anticancer effects by affecting the proliferation, apoptosis, autophagy, metastasis, chemotherapy and radiotherapy sensitivity, stemness, metabolism, angiogenesis, and immunity via multiple targeting. However, there is no systematical analysis on the interaction network of “multiple ingredients-multiple targets-multiple pathways” anticancer effects of Litchi. In this study, we summarized the confirmed anticancer ingredients and molecular targets of Litchi based on published articles and applied network pharmacology approach to explore the complex mechanisms underlying these effects from a perspective of system biology. The top ingredients, top targets, and top pathways of each anticancer function were identified using network pharmacology approach. Further intersecting analyses showed that Epigallocatechin gallate (EGCG), Gallic acid, Kaempferol, Luteolin, and Betulinic acid were the top ingredients which might be the key ingredients exerting anticancer function of Litchi, while BAX, BCL2, CASP3, and AKT1 were the top targets which might be the main targets underling the anticancer mechanisms of these top ingredients. These results provided references for further understanding and exploration of Litchi as therapeutics in cancer as well as the application of “Component Formula” based on Litchi’s effective ingredients.

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          Most cited references237

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          Factors involved in cancer metastasis: a better understanding to “seed and soil” hypothesis

          Metastasis has intrigued researchers for more than 100 years. Despite the development of technologies and therapeutic strategies, metastasis is still the major cause of cancer-related death until today. The famous “seed and soil” hypothesis is widely cited and accepted, and it still provides significant instructions in cancer research until today. To our knowledge, there are few reviews that comprehensively and correlatively focus on both the seed and soil factors involved in cancer metastasis; moreover, despite the fact that increasingly underlying mechanisms and concepts have been defined recently, previous perspectives are appealing but may be limited. Hence, we reviewed factors involved in cancer metastasis, including both seed and soil factors. By integrating new concepts with the classic hypothesis, we aim to provide a comprehensive understanding of the “seed and soil” hypothesis and to conceptualize the framework for understanding factors involved in cancer metastasis. Based on a dynamic overview of this field, we also discuss potential implications for future research and clinical therapeutic strategies.
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            Gallic acid, a major component of Toona sinensis leaf extracts, contains a ROS-mediated anti-cancer activity in human prostate cancer cells.

            Prostate cancer, the most frequently diagnosed malignancy in elderly males of the United States, has become a major health issue in Asia. Previous studies have demonstrated that leaf extracts of Toona sinensis Roem. contain cytotoxic activity on several cancer cells including prostate cancer cells. In this study, gallic acid is identified as the major anti-cancer compound in T. sinensis leaf extracts. It is cytotoxic to DU145 prostate cancer cells, through generation of reactive oxygen species (ROS) and mitochondria-mediated apoptosis, which were reversed by antioxidants catalase and N-acetylcysteine. Furthermore, gallic acid is shown to block the growth of DU145 cells at G2/M phases by activating Chk1 and Chk2 and inhibiting Cdc25C and Cdc2 activities. In addition, gallic acid has a synergistic effect with doxorubicin in suppressing the growth of DU145 cells. Taken together, our results suggest that gallic acid has the potential to be developed into an anti-prostate cancer drug and is worthy of further studies.
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              Green tea polyphenol EGCG suppresses lung cancer cell growth through upregulating miR-210 expression caused by stabilizing HIF-1α.

              (-)-Epigallocatechin-3-gallate (EGCG) has been reported to affect many cellular regulatory pathways. This study aims to determine whether EGCG could target microRNA (miRNA), one of the mechanisms for cells to achieve subtle change in multiple targets. We found that, in both human and mouse lung cancer cells in culture, EGCG specifically upregulated the expression of miR-210, a major miRNA regulated by HIF-1α. Furthermore, we found that overexpression of miR-210 led to reduced cell proliferation rate and anchorage-independent growth as well as reduced sensitivity to EGCG. On the mechanisms of miR-210 regulation by EGCG, we demonstrated that the regulation was mediated through the hypoxia-response element in miR-210 promoter. Consistently, the upregulation of miR-210 was found to be correlated with the stabilized HIF-1α in lung cancer cell lines after EGCG treatment. This EGCG-induced stabilization of HIF-1α was further shown by the stabilization of HA-tagged HIF-1α but not the P402A/P564A-mutated HIF-1α by EGCG, suggesting that EGCG targets the oxygen-dependent degradation (ODD) domain. Direct evidence was obtained by affinity binding assay showing that EGCG specifically binds HIF-1α with a K(d) = 3.47 μM. This result suggests that EGCG binding interferes with the hydroxylation of key Pro residues in the ODD domain, preventing HIF-1α from the Pro hydroxylation-dependent ubiquitination and subsequent proteosome-mediated degradation. In summary, our results demonstrated, for the first time, the elevation of miR-210 by EGCG in lung cancer cell lines and this is mediated by the stabilization of HIF-1α. This event contributes to the anticancer activity of EGCG.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                24 April 2020
                2020
                : 11
                : 451
                Affiliations
                [1] 1College of Pharmacy, Guangxi Medical University , Nanning, China
                [2] 2Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education & Center for Translational Medicine, Guangxi Medical University , Nanning, China
                [3] 3School of Preclinical Medicine, Guangxi Medical University , Nanning, China
                [4] 4Department of Surgery, University of Melbourne , Parkville, VIC, Australia
                Author notes

                Edited by: Jiang-Jiang Qin, Zhejiang Chinese Medical University, China

                Reviewed by: Yang Wang, Central South University, China; Guoyin Kai, Zhejiang Chinese Medical University, China; Denisa Margina, Carol Davila University of Medicine and Pharmacy, Romania

                *Correspondence: Zhiheng Su, suzhiheng915@ 123456126.com ; Hongwei Guo, hongweiguo@ 123456gxmu.edu.cn

                This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Pharmacology

                †These authors have contributed equally to this work

                Article
                10.3389/fphar.2020.00451
                7193898
                32390834
                00b39da5-1bc3-4157-a4b3-4ec7e7879548
                Copyright © 2020 Cao, Han, Li, Chen, Zhu, Su and Guo

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 02 October 2019
                : 23 March 2020
                Page count
                Figures: 7, Tables: 2, Equations: 0, References: 260, Pages: 23, Words: 8093
                Categories
                Pharmacology
                Original Research

                Pharmacology & Pharmaceutical medicine
                litchi,cancer,multi-ingredients,multi-targets,network pharmacology

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