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      Levobupivacaine Induces Ferroptosis by miR-489-3p/SLC7A11 Signaling in Gastric Cancer

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          Abstract

          Gastric cancer is one of the most the prevalent malignancies and the therapeutic strategies for patients with gastric cancer remains limited. Local anesthetic levobupivacaine has demonstrated potential anti-cancer property, but its correlation with gastric cancer and ferroptosis is poor understood. Here, we identified the novel function of levobupivacaine in regulating ferroptosis of gastric cancer cells. The treatment of levobupivacaine suppressed gastric cancer cell viabilities and Edu-positive cell proportions. The gastric cancer cell growth was reduced by levobupivacaine in vivo. Moreover, the treatment of levobupivacaine enhanced erastin-induced inhibitory impact on gastric cancer cell viabilities. The levels of Fe 2+/iron and lipid ROS were induced by levobupivacaine in erastin and RSL3-stimulated gastric cancer cells. levobupivacaine-upregulated miR-489-3p enhanced ferroptosis of gastric cancer cells by targeting SLC7A11. MiR-489-3p was involved in levobupivacaine-induced ferroptosis of gastric cancer cells. Levobupivacaine/miR-489-3p/SLC7A11 axis attenuates gastric cancer cell proliferation in vitro. Therefore, we concluded that the local anesthetic levobupivacaine induced ferroptosis of gastric cancer cells to repress gastric cancer cell growth by miR-489-3p/SLC7A11 axis.

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          Ferroptosis: an iron-dependent form of nonapoptotic cell death.

          Scott J. Dixon, Kathryn Lemberg, Michael Lamprecht … (2012)
          Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Gastric cancer

            Elizabeth Smyth, Magnus Nilsson, Heike I Grabsch … (2020)
            Gastric cancer is the fifth most common cancer and the third most common cause of cancer death globally. Risk factors for the condition include Helicobacter pylori infection, age, high salt intake, and diets low in fruit and vegetables. Gastric cancer is diagnosed histologically after endoscopic biopsy and staged using CT, endoscopic ultrasound, PET, and laparoscopy. It is a molecularly and phenotypically highly heterogeneous disease. The main treatment for early gastric cancer is endoscopic resection. Non-early operable gastric cancer is treated with surgery, which should include D2 lymphadenectomy (including lymph node stations in the perigastric mesentery and along the celiac arterial branches). Perioperative or adjuvant chemotherapy improves survival in patients with stage 1B or higher cancers. Advanced gastric cancer is treated with sequential lines of chemotherapy, starting with a platinum and fluoropyrimidine doublet in the first line; median survival is less than 1 year. Targeted therapies licensed to treat gastric cancer include trastuzumab (HER2-positive patients first line), ramucirumab (anti-angiogenic second line), and nivolumab or pembrolizumab (anti-PD-1 third line).
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              MicroRNA therapeutics: towards a new era for the management of cancer and other diseases

              Rajesha Rupaimoole, Frank J Slack (2017)
              MicroRNAs (miRNAs) are small non-coding RNAs that can modulate mRNA expression. Insights into the roles of miRNAs in development and disease have led to the development of new therapeutic approaches that are based on miRNA mimics or agents that inhibit their functions (antimiRs), and the first such approaches have entered the clinic. This Review discusses the role of different miRNAs in cancer and other diseases, and provides an overview of current miRNA therapeutics in the clinic.
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Pharmacol
                Journal ID (iso-abbrev): Front Pharmacol
                Journal ID (publisher-id): Front. Pharmacol.
                Title: Frontiers in Pharmacology
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1663-9812
                Publication date (Electronic): 09 June 2021
                Publication date Collection: 2021
                Volume: 12
                Electronic Location Identifier: 681338
                Affiliations
                Department of Anesthesia, Cangzhou Central Hospital, Cangzhou, China
                Author notes

                Edited by: Cyril Corbet, Fonds National de la Recherche Scientifique (FNRS), Belgium

                Reviewed by: Hongmei Cui, Lanzhou University, China

                Lana Nezic, University of Banja Luka, Bosnia and Herzegovina

                De Jun Ding, Weifang Medical University, China

                *Correspondence: Chun-Hua Zhu, huaqikan70081@ 123456163.com

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

                Article
                Publisher ID: 681338
                DOI: 10.3389/fphar.2021.681338
                PMC ID: 8220201
                PubMed ID: 34177591
                SO-VID: 0d2d32ef-dfba-4b2f-bba0-3558114e0347
                Copyright © Copyright © 2021 Mao, Zhu, Nie, Yu and Wang.
                License:

                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
                Date received : 16 March 2021
                Date accepted : 30 April 2021
                Categories
                Subject: Pharmacology
                Subject: Original Research

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: gastric cancer,levobupivacaine,ferroptosis,mir-489-3p,slc7a11
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: gastric cancer, levobupivacaine, ferroptosis, mir-489-3p, slc7a11

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