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      Cymensifin A: a promising pharmaceutical candidate to defeat lung cancer via cellular reactive oxygen species-mediated apoptosis

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          Abstract

          Background: The upgrade of natural products for cancer treatment is essential since current anticancer drugs still pose severe side effects. Cymensifin A (Cym A) isolated from an orchid Cymbidium ensifolium has shown its potential to induce the death of several cancer cells; however, its underlying molecular mechanisms are hitherto unknown.

          Methods: Here, we conducted a set of in vitro preliminary tests to assess the cytotoxic effects of Cym A on non-small-cell lung cancer (NSCLC) cells (A549, H23, H292, and H460). A flow cytometry system and Western blot analyses were employed to unveil molecular mechanisms underlying cancer cell apoptosis caused by Cym A.

          Results: Cym A at 25–50 μM caused the death of all NSCLC cells tested, and its cytotoxicity was comparable to cisplatin, a currently used anticancer drug. The compound induced apoptosis of all NSCLC cells in a dose-dependent manner (5–50 μM), proven by flow cytometry, but H460 cells showed more resistance compared to other cells tested. Cym A-treated H460 cells demonstrated increased reactive oxygen species (ROS) and downregulated antioxidants (catalase, superoxide dismutase, and thioredoxin). The compound also upregulated the tumor suppressor P53 and the pro-apoptotic protein BAX but downregulated pro-survival proteins (BCL-2 and MCL-1) and deactivated survival signals (AKT and ERK) in H460 cells. Cym A was proven to trigger cellular ROS formation, but P53 and BAX were 2-fold more activated by Cym A compared to those treated with hydrogen peroxide. Our findings also supported that Cym A exerted its roles in the downregulation of nuclear factor erythroid 2–related factor 2 (a regulator of cellular antioxidant activity) and the increased levels of cleaved poly (ADP-ribose) polymerase (PARP) and cleaved caspase 3/7 during apoptosis.

          Conclusion: We propose that Cym A induces lung cancer cell death via ROS-mediated apoptosis, while the modulation of cellular ROS/antioxidant activity, the upregulation of P53 and BAX, the downregulation or deactivation of BCL-2, MCL-1, AKT, and ERK, and the increased cleavage of PARP and caspase 3/7, were the elucidated underlying molecular mechanisms of this phytochemical. The compound can be a promising candidate for future anticancer drug development.

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          Role of nrf2 in oxidative stress and toxicity.

          Qiang Ma (2013)
          Organismal life encounters reactive oxidants from internal metabolism and environmental toxicant exposure. Reactive oxygen and nitrogen species cause oxidative stress and are traditionally viewed as being harmful. On the other hand, controlled production of oxidants in normal cells serves useful purposes to regulate signaling pathways. Reactive oxidants are counterbalanced by complex antioxidant defense systems regulated by a web of pathways to ensure that the response to oxidants is adequate for the body's needs. A recurrent theme in oxidant signaling and antioxidant defense is reactive cysteine thiol-based redox signaling. The nuclear factor erythroid 2-related factor 2 (Nrf2) is an emerging regulator of cellular resistance to oxidants. Nrf2 controls the basal and induced expression of an array of antioxidant response element-dependent genes to regulate the physiological and pathophysiological outcomes of oxidant exposure. This review discusses the impact of Nrf2 on oxidative stress and toxicity and how Nrf2 senses oxidants and regulates antioxidant defense.
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            Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?

            Increased generation of reactive oxygen species (ROS) and an altered redox status have long been observed in cancer cells, and recent studies suggest that this biochemical property of cancer cells can be exploited for therapeutic benefits. Cancer cells in advanced stage tumours frequently exhibit multiple genetic alterations and high oxidative stress, suggesting that it might be possible to preferentially eliminate these cells by pharmacological ROS insults. However, the upregulation of antioxidant capacity in adaptation to intrinsic oxidative stress in cancer cells can confer drug resistance. Abrogation of such drug-resistant mechanisms by redox modulation could have significant therapeutic implications. We argue that modulating the unique redox regulatory mechanisms of cancer cells might be an effective strategy to eliminate these cells.
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              Drug Resistance in Cancer: An Overview

              Cancers have the ability to develop resistance to traditional therapies, and the increasing prevalence of these drug resistant cancers necessitates further research and treatment development. This paper outlines the current knowledge of mechanisms that promote or enable drug resistance, such as drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, and the epithelial-mesenchymal transition, as well as how inherent tumor cell heterogeneity plays a role in drug resistance. It also describes the epigenetic modifications that can induce drug resistance and considers how such epigenetic factors may contribute to the development of cancer progenitor cells, which are not killed by conventional cancer therapies. Lastly, this review concludes with a discussion on the best treatment options for existing drug resistant cancers, ways to prevent the formation of drug resistant cancers and cancer progenitor cells, and future directions of study.
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                Author and article information

                Contributors
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                Role: Role: Role: Role: Role:
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                URI : https://loop.frontiersin.org/people/399102/overviewRole:
                URI : https://loop.frontiersin.org/people/590087/overviewRole: Role: Role:
                URI : https://loop.frontiersin.org/people/2633173/overviewRole: Role: Role: Role: Role: Role: Role: Role: Role: Role:
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                11 April 2024
                2024
                : 15
                : 1361085
                Affiliations
                [1] 1 Pharmaceutical Sciences and Technology Program , Faculty of Pharmaceutical Sciences , Chulalongkorn University , Bangkok, Thailand
                [2] 2 Department of Biochemistry and Microbiology , Faculty of Pharmaceutical Sciences , Chulalongkorn University , Bangkok, Thailand
                [3] 3 Department of Pharmacognosy and Pharmaceutical Botany , Faculty of Pharmaceutical Sciences , Chulalongkorn University , Bangkok, Thailand
                [4] 4 Center of Excellence in Natural Products for Ageing and Chronic Diseases , Faculty of Pharmaceutical Sciences , Chulalongkorn University , Bangkok, Thailand
                [5] 5 Department of Pharmacology and Physiology , Faculty of Pharmaceutical Sciences , Chulalongkorn University , Bangkok, Thailand
                [6] 6 Center of Excellence in Cancer Cell and Molecular Biology , Faculty of Pharmaceutical Sciences , Chulalongkorn University , Bangkok, Thailand
                [7] 7 Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF) , University of Palermo , Palermo, Italy
                Author notes

                Edited by: Jianqiang Xu, Dalian University of Technology, China

                Reviewed by: Magnus Olsson, Karolinska Institutet (KI), Sweden

                Domenico D’Arca, University of Modena and Reggio Emilia, Italy

                *Correspondence: Chatchai Chaotham, cchoatham@ 123456gmail.com
                Article
                1361085
                10.3389/fphar.2024.1361085
                11043475
                38666017
                6dd4f889-91ad-40d3-821a-cb567b8b1e41
                Copyright © 2024 Soares, Khine, Sritularak, Chanvorachote, Alduina, Sungthong and Chaotham.

                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
                : 24 December 2023
                : 29 March 2024
                Funding
                The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was funded by the Thailand Science Research and Innovation Fund Chulalongkorn University.
                Categories
                Pharmacology
                Original Research
                Custom metadata
                Pharmacology of Anti-Cancer Drugs

                Pharmacology & Pharmaceutical medicine
                lung cancer,ros,apoptosis,mitochondrial outer membrane permeabilization,dna damage,cymensifin a,orchid

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