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      Olaparib synergizes with arsenic trioxide by promoting apoptosis and ferroptosis in platinum-resistant ovarian cancer

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          Abstract

          Poly (ADP-ribose) polymerase (PARP) inhibitors are efficacious in treating platinum-sensitive ovarian cancer (OC), but demonstrate limited efficiency in patients with platinum-resistant OC. Thus, further investigations into combined strategies that enhance the response to PARP inhibitors (PARPi) in platinum-resistant OC are required. The present study aimed to investigate the combined therapy of arsenic trioxide (ATO) with olaparib, a common PARPi, and determine how this synergistic cytotoxicity works in platinum-resistant OC cells. Functional assays demonstrated that the combined treatment of olaparib with ATO significantly suppressed cell proliferation and colony formation, and enhanced DNA damage as well as cell apoptosis in A2780-CIS and SKOV3-CIS cell lines. Results of the present study also demonstrated that a combination of olaparib with ATO increased lipid peroxidation and eventually triggered ferroptosis. Consistently, the combined treatment synergistically suppressed tumor growth in mice xenograft models. Mechanistically, ATO in combination with olaparib activated the AMPK α pathway and suppressed the expression levels of stearoyl-CoA desaturase 1 (SCD1). Collectively, results of the present study demonstrated that treatment with ATO enhanced the effects of olaparib in platinum-resistant OC.

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          Cancer Statistics, 2021

          Rebecca Siegel, Kimberly D Miller, Hannah Fuchs … (2021)
          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2017) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2018) were collected by the National Center for Health Statistics. In 2021, 1,898,160 new cancer cases and 608,570 cancer deaths are projected to occur in the United States. After increasing for most of the 20th century, the cancer death rate has fallen continuously from its peak in 1991 through 2018, for a total decline of 31%, because of reductions in smoking and improvements in early detection and treatment. This translates to 3.2 million fewer cancer deaths than would have occurred if peak rates had persisted. Long-term declines in mortality for the 4 leading cancers have halted for prostate cancer and slowed for breast and colorectal cancers, but accelerated for lung cancer, which accounted for almost one-half of the total mortality decline from 2014 to 2018. The pace of the annual decline in lung cancer mortality doubled from 3.1% during 2009 through 2013 to 5.5% during 2014 through 2018 in men, from 1.8% to 4.4% in women, and from 2.4% to 5% overall. This trend coincides with steady declines in incidence (2.2%-2.3%) but rapid gains in survival specifically for nonsmall cell lung cancer (NSCLC). For example, NSCLC 2-year relative survival increased from 34% for persons diagnosed during 2009 through 2010 to 42% during 2015 through 2016, including absolute increases of 5% to 6% for every stage of diagnosis; survival for small cell lung cancer remained at 14% to 15%. Improved treatment accelerated progress against lung cancer and drove a record drop in overall cancer mortality, despite slowing momentum for other common cancers.
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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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              Ferroptosis: mechanisms, biology and role in disease

              Xuejun Jiang, Brent Stockwell, Marcus Conrad (2021)
              The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future ferroptosis research.
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                Author and article information

                Contributors
                Weiguo Lu:
                ORCID: http://orcid.org/0000-0003-2062-7145
                lbwg@zju.edu.cn
                Junfen Xu:
                ORCID: http://orcid.org/0000-0002-2377-0775
                xjfzu@zju.edu.cn
                Journal
                Journal ID (nlm-ta): Cell Death Dis
                Journal ID (iso-abbrev): Cell Death Dis
                Title: Cell Death & Disease
                Publisher: Nature Publishing Group UK (London )
                ISSN (Electronic): 2041-4889
                Publication date (Electronic): 27 September 2022
                Publication date PMC-release: 27 September 2022
                Publication date Collection: September 2022
                Volume: 13
                Issue: 9
                Electronic Location Identifier: 826
                Affiliations
                [1 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Women’s Reproductive Health Laboratory of Zhejiang Province, Women’s Hospital, , Zhejiang University School of Medicine, ; 310006 Hangzhou, Zhejiang China
                [2 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Department of Gynecologic Oncology, Women’s Hospital, , Zhejiang University School of Medicine, ; 310006 Hangzhou, Zhejiang China
                [3 ]GRID grid.13402.34, ISNI 0000 0004 1759 700X, Cancer center, , Zhejiang University, ; 310058 Hangzhou, Zhejiang China
                Author information
                http://orcid.org/0000-0003-2062-7145
                http://orcid.org/0000-0002-2377-0775
                Article
                Publisher ID: 5257
                DOI: 10.1038/s41419-022-05257-y
                PMC ID: 9513087
                PubMed ID: 36163324
                SO-VID: bbd5a1a5-383e-4393-809c-6a2f3c8331f8
                Copyright © © The Author(s) 2022
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 25 April 2022
                Date revision received : 9 September 2022
                Date accepted : 12 September 2022
                Funding
                Funded by: A Project Supported by Scientific Research Fund of Zhejiang Provincial Education Department (Y202148361)
                Funded by: Fundamental Research Funds for the Central Universities (No. 2019QNA7035 and 2021FZZX001-43) Beijing Kanghua Foundation for the Development of Traditional Chinese and Western Medicine (KH-2021-LLZX-016)
                Categories
                Subject: Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2022

                ScienceOpen disciplines: Cell biology
                Keywords: cell death,targeted therapies,ovarian cancer
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: cell death, targeted therapies, ovarian cancer

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