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      Isodeoxyelephantopin Inactivates Thioredoxin Reductase 1 and Activates ROS-Mediated JNK Signaling Pathway to Exacerbate Cisplatin Effectiveness in Human Colon Cancer Cells

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          Abstract

          Colon cancer is one of the leading causes of cancer-related death in the world. The development of new drugs and therapeutic strategies for patients with colon cancer are urgently needed. Isodeoxyelephantopin (ESI), a sesquiterpene lactone isolated from the medicinal plant Elephantopus scaber L., has been reported to exert antitumor effects on several cancer cells. However, the molecular mechanisms underlying the action of ESI is still elusive. In the present study, we found that ESI potently suppressed cell proliferation in human colon cancer cells. Furthermore, our results showed that ESI treatment markedly increased cellular reactive oxygen species (ROS) levels by inhibiting thioredoxin reductase 1 (TrxR1) activity, which leads to activation of the JNK signaling pathway and eventually cell death in HCT116 and RKO cells. Importantly, we found that ESI markedly enhanced cisplatin-induced cytotoxicity in HCT116 and RKO cells. Combination of ESI and cisplatin significantly increased the production of ROS, resulting in activation of the JNK signaling pathway in HCT116 and RKO cells. In vivo, we found that ESI combined with cisplatin significantly suppressed tumor growth in HCT116 xenograft models. Together, our study provide a preclinical proof-of-concept for ESI as a potential strategy for colon cancer treatment.

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          Most cited references54

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          ROS function in redox signaling and oxidative stress.

          Oxidative stress refers to elevated intracellular levels of reactive oxygen species (ROS) that cause damage to lipids, proteins and DNA. Oxidative stress has been linked to a myriad of pathologies. However, elevated ROS also act as signaling molecules in the maintenance of physiological functions--a process termed redox biology. In this review we discuss the two faces of ROS--redox biology and oxidative stress--and their contribution to both physiological and pathological conditions. Redox biology involves a small increase in ROS levels that activates signaling pathways to initiate biological processes, while oxidative stress denotes high levels of ROS that result in damage to DNA, protein or lipids. Thus, the response to ROS displays hormesis, given that the opposite effect is observed at low levels compared with that seen at high levels. Here, we argue that redox biology, rather than oxidative stress, underlies physiological and pathological conditions. Copyright © 2014 Elsevier Ltd. All rights reserved.
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            Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial

            Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma. This study reports on the safety and efficacy of the docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) as a perioperative therapy for patients with locally advanced, resectable tumours.
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              ROS and the DNA damage response in cancer

              Reactive oxygen species (ROS) are a group of short-lived, highly reactive, oxygen-containing molecules that can induce DNA damage and affect the DNA damage response (DDR). There is unequivocal pre-clinical and clinical evidence that ROS influence the genotoxic stress caused by chemotherapeutics agents and ionizing radiation. Recent studies have provided mechanistic insight into how ROS can also influence the cellular response to DNA damage caused by genotoxic therapy, especially in the context of Double Strand Breaks (DSBs). This has led to the clinical evaluation of agents modulating ROS in combination with genotoxic therapy for cancer, with mixed success so far. These studies point to context dependent outcomes with ROS modulator combinations with Chemotherapy and radiotherapy, indicating a need for additional pre-clinical research in the field. In this review, we discuss the current knowledge on the effect of ROS in the DNA damage response, and its clinical relevance.
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                Author and article information

                Contributors
                Journal
                Front Cell Dev Biol
                Front Cell Dev Biol
                Front. Cell Dev. Biol.
                Frontiers in Cell and Developmental Biology
                Frontiers Media S.A.
                2296-634X
                22 September 2020
                2020
                : 8
                : 580517
                Affiliations
                [1] 1The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical University , Wenzhou, China
                [2] 2Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University , Wenzhou, China
                [3] 3Zhuji Institute of Biomedicine, School of Pharmaceutical Sciences, Wenzhou Medical University , Zhuji, China
                [4] 4Wenzhou University-Wenzhou Medical University Collaborative Innovation Center of Biomedical , Wenzhou, China
                Author notes

                Edited by: José Díaz-Chávez, National Institute of Cancerology (INCAN), Mexico

                Reviewed by: Parvez Khan, University of Nebraska Medical Center, United States; Yulin Ren, The Ohio State University, United States

                *Correspondence: Peng Zou, zoupeng@ 123456wmu.edu.cn

                These authors have contributed equally to this work

                This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Cell and Developmental Biology

                Article
                10.3389/fcell.2020.580517
                7536313
                33072762
                a8ea6bab-0cf3-4cd3-ad9a-da4a1b2c4de5
                Copyright © 2020 Hong, Chen, Wu, Wu, Shen, Zheng, Shao, Lu, Liu, Chen, Liang, Cai, Zou and Xia.

                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
                : 06 July 2020
                : 28 August 2020
                Page count
                Figures: 7, Tables: 0, Equations: 0, References: 60, Pages: 13, Words: 0
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Categories
                Cell and Developmental Biology
                Original Research

                isodeoxyelephantopin,oxidative stress,thioredoxin reductase 1,cisplatin,jnk

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