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      Targeting ferroptosis in osteosarcoma

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          Highlights

          • Targeting ferroptosis in osteosarcoma.

          • A new strategy for the treatment of osteosarcoma.

          • A non-traditional mode of regulated cell death.

          Abstract

          Osteosarcoma (OS) is the most common primary bone tumour in children and adolescents, with high degree of malignancy and an extremely poor prognosis. Ferroptosis, a non-traditional mode of regulated cell death (RCD) characterised by iron-dependent accumulation of lipid reactive oxygen species (ROS), is closely associated with a variety of cancers. It has been demonstrated that ferroptosis can regulate OS progression and exert an essential role in the treatment of OS, which is potentially of great value. By targeting ferroptosis in OS, the present review article summarises the relevant mechanisms and therapeutic applications along with discussing current limitations and future directions, which may provide a new strategy for the treatment of OS.

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          Most cited references87

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          Cancer statistics, 2020

          Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population-based cancer occurrence. Incidence data (through 2016) 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 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long-term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008-2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single-year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long-term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.
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            Ferroptosis: an iron-dependent form of nonapoptotic cell death.

            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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              Regulation of ferroptotic cancer cell death by GPX4.

              Ferroptosis is a form of nonapoptotic cell death for which key regulators remain unknown. We sought a common mediator for the lethality of 12 ferroptosis-inducing small molecules. We used targeted metabolomic profiling to discover that depletion of glutathione causes inactivation of glutathione peroxidases (GPXs) in response to one class of compounds and a chemoproteomics strategy to discover that GPX4 is directly inhibited by a second class of compounds. GPX4 overexpression and knockdown modulated the lethality of 12 ferroptosis inducers, but not of 11 compounds with other lethal mechanisms. In addition, two representative ferroptosis inducers prevented tumor growth in xenograft mouse tumor models. Sensitivity profiling in 177 cancer cell lines revealed that diffuse large B cell lymphomas and renal cell carcinomas are particularly susceptible to GPX4-regulated ferroptosis. Thus, GPX4 is an essential regulator of ferroptotic cancer cell death. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                J Bone Oncol
                J Bone Oncol
                Journal of Bone Oncology
                Elsevier
                2212-1366
                2212-1374
                12 July 2021
                October 2021
                12 July 2021
                : 30
                : 100380
                Affiliations
                [a ]Department of Orthopedics, The Fourth Hospital of Hebei Medical University, 12 Health Road, Shijiazhuang, Hebei 050011, PR China
                [b ]Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, Hebei 050011, PR. China
                Author notes
                [* ]Corresponding author. helinfeng0311@ 123456163.com
                [1]

                ORCID ID: Jiazheng Zhao 0000-0001-5059-1054

                [2]

                ORCID ID: Helin Feng 0000-0002-7260-5485

                Article
                S2212-1374(21)00035-X 100380
                10.1016/j.jbo.2021.100380
                8319509
                34345580
                9bb9dc4a-9b95-4afb-9446-a5da3caecf0b
                © 2021 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 6 May 2021
                : 3 July 2021
                : 5 July 2021
                Categories
                Review Article

                ferroptosis,osteosarcoma,treatment,iron,reactive oxygen species

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