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Tiwari A, Yadav P, Shah AA, Rana R, Yadav P, Mishra K, Tripathi S, Kothuri N, Verma S, Kashyap A, Jaiswal S, Verma S, Mugale MN, Chourasia MK. Designing pegylated dextran sheathed doxorubicin loaded iron nanoparticles against premenopausal breast cancer. Int J Biol Macromol 2025; 307:141874. [PMID: 40064263 DOI: 10.1016/j.ijbiomac.2025.141874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 02/27/2025] [Accepted: 03/07/2025] [Indexed: 03/18/2025]
Abstract
Premenopausal women, often iron-deficient, face a heightened risk of breast cancer. Magnetic nanoparticles (MNPs) show promise for cancer therapy but are limited by challenges in pharmacokinetics, biocompatibility, and magnetic property stability, leading to reduced efficacy and resistance. To overcome these hurdles, a double-shelled magnetic nanoparticle (DOX-RA-MNP) system was developed for pH-sensitive delivery of Retinoic acid and Doxorubicin using an immunomodulatory polymeric approach. Optimized by using a QbD framework, the formulation demonstrated ideal size, polydispersity index, zeta potential, and enhanced doxorubicin loading. The formulation depicted sustained drug release with enhanced release at tumor pH. In vitro studies on MDA-MB-231 cells revealed improved cytotoxicity, cellular uptake, G2 phase cell cycle arrest, mitochondrial membrane depolarization, and PgP protein inhibition. In in vivo, the system showed significant tumor regression, favorable pharmacokinetics, biodistribution, and safety, with lower hemolysis and improved survival rates. The biochemical studies provide insights about the role of ferroptosis increasing reactive oxygen species (ROS) level and immunomodulatory effects. Further, the lower hemolysis and enhanced survival of animals confirmed safety of the developed formulation. These findings suggest the DOX-RA-MNP system effectively targets and localizes drugs, reducing toxicity and offering a potent strategy for breast cancer treatment.
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Affiliation(s)
- Amrendra Tiwari
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Pavan Yadav
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Aarti Abhishek Shah
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Rafquat Rana
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Pooja Yadav
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Keerti Mishra
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Shourya Tripathi
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Naresh Kothuri
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Sonia Verma
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Amit Kashyap
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Srishty Jaiswal
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India
| | - Shobhit Verma
- Division of Toxicology & Experiment Medicine, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India
| | - Madhav N Mugale
- Division of Toxicology & Experiment Medicine, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India
| | - Manish K Chourasia
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India.
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2
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Ribeiro KS, Karmakar E, Park C, Garg R, Kung GP, Kadakia I, Gopianand JS, Arun T, Kisselev O, Gnana-Prakasam JP. Iron Regulates Cellular Proliferation by Enhancing the Expression of Glucose Transporter GLUT3 in the Liver. Cells 2024; 13:1147. [PMID: 38994998 PMCID: PMC11240476 DOI: 10.3390/cells13131147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 07/01/2024] [Accepted: 07/02/2024] [Indexed: 07/13/2024] Open
Abstract
Iron is often accumulated in the liver during pathological conditions such as cirrhosis and cancer. Elevated expression of glucose transporters GLUT1 and GLUT3 is associated with reduced overall survival in patients with hepatocellular carcinoma. However, it is not known whether iron can regulate glucose transporters and contribute to tumor proliferation. In the present study, we found that treatment of human liver cell line HepG2 with ferric ammonium citrate (FAC) resulted in a significant upregulation of GLUT3 mRNA and protein in a dose-dependent manner. Similarly, iron accumulation in mice fed with high dietary iron as well as in mice injected intraperitoneally with iron dextran enhanced the GLUT3 expression drastically in the liver. We demonstrated that iron-induced hepatic GLUT3 upregulation is mediated by the LKB1/AMPK/CREB1 pathway, and this activation was reversed when treated with iron chelator deferiprone. In addition, inhibition of GLUT3 using siRNA prevented iron-mediated increase in the expression of cell cycle markers and cellular hyperproliferation. Furthermore, exogenous sodium beta-hydroxybutyrate treatment prevented iron-mediated hepatic GLUT3 activation both in vitro and in vivo. Together, these results underscore the importance of iron, AMPK, CREB1 and GLUT3 pathways in cell proliferation and highlight the therapeutic potential of sodium beta-hydroxybutyrate in hepatocellular carcinoma with high GLUT3 expression.
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Al Khamees M, Alqurain AA, Alsaleh AA, Alhashem YA, AlSaffar N, Alibrahim NN, Aljunibi FA, Alradwan Z, Almohammade N, AlAlwan B. Prevalence of Iron Deficiency and its Association With Breast Cancer in Premenopausal Compared to Postmenopausal Women in Al Ahsa, Saudi Arabia. Cancer Inform 2023; 22:11769351231172589. [PMID: 37223318 PMCID: PMC10201173 DOI: 10.1177/11769351231172589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 04/12/2023] [Indexed: 05/25/2023] Open
Abstract
Iron is an essential cofactor needed for normal functions of various enzymes and its depletion lead to increase DNA damage, genomic instability, deteriorate innate, adaptive immunity, and promote tumor development. It is also linked to tumorigenesis of breast cancer cells through enhancing mammary tumor growth and metastasis. There is insufficient data describing this association in Saudi Arabia. This study aims to determine the prevalence of iron deficiency and its association with breast cancer among premenopausal and postmenopausal women referred for breast cancer screening center in Al Ahsa, Eastern Province of Saudi Arabia. Age, hemoglobin level, iron level, history of anemia, or iron deficiency were collected from patients' medical records. The included participants were grouped based on their age into premenopausal (<50 years) or postmenopausal (⩾50 years). The definition of low Hb implemented (Hb below 12 g/dL) and low total serum Iron levels (below 8 μmol/L). Logistic regression test was used to compute the association between having a positive cancer screening test (radiological or histocytological) and participant's lab results. The results are presented as odds ratios and 95% confidence intervals. Thrree hundred fifty-seven women were included, 77% (n = 274) of them were premenopausal. This group cases had more history of iron deficiency (149 [60%] vs 25 (30%), P = .001) compared to those in the postmenopausal group. The risk of having a positive radiological cancer screening test was associated with age (OR = 1.04, 95% CI 1.02-1.06), but negatively was associated with iron level (OR = 0.9, 95% CI 0.86-0.97) among the entire cohort. This study is the first to propose an association between iron deficiency and breast cancer among Saudi young females. This could suggest iron level as a new risk factor that may be used by clinicians to assess breast cancer risk.
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Affiliation(s)
- Mohammad Al Khamees
- Clinical Laboratory Department, King
Fahad Hospital Hoffuf, Hoffuf, Saudi Arabia
| | - Aymen A Alqurain
- Department of Pharmacy, Mohammed
Al-Mana College for Medical Sciences, Dammam, Saudi Arabia
| | - Abdulmonem A Alsaleh
- Medical Laboratory Science Department,
Mohammed Al-Mana College for Medical Sciences, Dammam, Saudi Arabia
| | - Yousef A Alhashem
- Medical Laboratory Science Department,
Mohammed Al-Mana College for Medical Sciences, Dammam, Saudi Arabia
| | - Nida AlSaffar
- Medical Laboratory Science Department,
Mohammed Al-Mana College for Medical Sciences, Dammam, Saudi Arabia
| | - Noura N Alibrahim
- Medical Laboratory Science Department,
Mohammed Al-Mana College for Medical Sciences, Dammam, Saudi Arabia
| | - Fardus A Aljunibi
- Medical Laboratory Science Department,
Mohammed Al-Mana College for Medical Sciences, Dammam, Saudi Arabia
| | - Zaheda Alradwan
- Medical Laboratory Science Department,
Mohammed Al-Mana College for Medical Sciences, Dammam, Saudi Arabia
| | - Nesreen Almohammade
- Foundation Year Department, Mohammed
Al-Mana College for Medical Sciences, Dammam, Saudi Arabia
| | - Bader AlAlwan
- Medical Laboratory Science Department,
Mohammed Al-Mana College for Medical Sciences, Dammam, Saudi Arabia
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Xu L, Liu Y, Chen X, Zhong H, Wang Y. Ferroptosis in life: To be or not to be. Biomed Pharmacother 2023; 159:114241. [PMID: 36634587 DOI: 10.1016/j.biopha.2023.114241] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/06/2023] [Accepted: 01/09/2023] [Indexed: 01/12/2023] Open
Abstract
Ferroptosis is a novel type of programmed cell death, characterized by a dysregulated iron metabolism and accumulation of lipid peroxides. It features the alteration of mitochondria and aberrant accumulation of excessive iron as well as loss of the cysteine-glutathione-GPX4 axis. Eventually, the accumulated lipid peroxides result in lethal damage to the cells. Ferroptosis is induced by the overloading of iron and the accumulation of ROS and can be inhibited by the activation of the GPX4 pathway, FS1-CoQ10 pathway, GCH1-BH4 pathway, and the DHODH pathway, it is also regulated by the oncogenes and tumor suppressors. Ferroptosis involves various physiological and pathological processes, and increasing evidence indicates that ferroptosis play a critical role in cancers and other diseases. It inhibits the proliferation of malignant cells in various types of cancers and inducing ferroptosis may become a new method of cancer treatment. Many inhibitors targeting the key factors of ferroptosis such as SLC7A11, GPX4, and iron overload have been developed. The application of ferroptosis is mainly divided into two directions, i.e. to avoid ferroptosis in healthy cells and selectively induce ferroptosis in cancers. In this review, we provide a critical analysis of the concept, and regulation pathways of ferroptosis and explored its roles in various diseases, we also summarized the compounds targeting ferroptosis, aiming to promote the speed of clinical use of ferroptosis induction in cancer treatment.
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Affiliation(s)
- Ling Xu
- Department of Internal Medicine of Traditional Chinese Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China.
| | - Yu'e Liu
- Tongji University Cancer Center, Shanghai Tenth People's Hospital of Tongji University, School of Medicine, Tongji University, Shanghai 200092, China.
| | - Xi Chen
- Xi Chen, Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Hua Zhong
- Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, HI, USA 96813
| | - Yi Wang
- Department of Critical Care Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
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5
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Kouroumalis E, Tsomidis I, Voumvouraki A. Iron as a therapeutic target in chronic liver disease. World J Gastroenterol 2023; 29:616-655. [PMID: 36742167 PMCID: PMC9896614 DOI: 10.3748/wjg.v29.i4.616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/03/2022] [Accepted: 12/31/2022] [Indexed: 01/20/2023] Open
Abstract
It was clearly realized more than 50 years ago that iron deposition in the liver may be a critical factor in the development and progression of liver disease. The recent clarification of ferroptosis as a specific form of regulated hepatocyte death different from apoptosis and the description of ferritinophagy as a specific variation of autophagy prompted detailed investigations on the association of iron and the liver. In this review, we will present a brief discussion of iron absorption and handling by the liver with emphasis on the role of liver macrophages and the significance of the iron regulators hepcidin, transferrin, and ferritin in iron homeostasis. The regulation of ferroptosis by endogenous and exogenous mod-ulators will be examined. Furthermore, the involvement of iron and ferroptosis in various liver diseases including alcoholic and non-alcoholic liver disease, chronic hepatitis B and C, liver fibrosis, and hepatocellular carcinoma (HCC) will be analyzed. Finally, experimental and clinical results following interventions to reduce iron deposition and the promising manipulation of ferroptosis will be presented. Most liver diseases will be benefited by ferroptosis inhibition using exogenous inhibitors with the notable exception of HCC, where induction of ferroptosis is the desired effect. Current evidence mostly stems from in vitro and in vivo experimental studies and the need for well-designed future clinical trials is warranted.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71003, Greece
| | - Ioannis Tsomidis
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
| | - Argyro Voumvouraki
- First Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54621, Greece
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6
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Basak T, Kanwar RK. Iron imbalance in cancer: Intersection of deficiency and overload. Cancer Med 2022; 11:3837-3853. [PMID: 35460205 PMCID: PMC9582687 DOI: 10.1002/cam4.4761] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 02/09/2022] [Accepted: 02/25/2022] [Indexed: 12/19/2022] Open
Abstract
Iron, an essential trace element, plays a complex role in tumour biology. While iron causes cancer clearance through toxic free radical generation, iron‐induced free radical flux also acts as a cancer promoter. These fates majorly guided through cellular response towards pro‐oxidant and antioxidant settings in a tumour microenvironment, designate iron‐induced oxidative stress as a common yet paradoxical factor in pro‐tumorigenesis as well as anti‐tumorigenesis, posing a challenge to laying down iron thresholds favouring tumour clearance. Additionally, complexity of iron's association with carcinogenesis has been extended to iron‐induced ROS's involvement in states of both iron deficiency and overload, conditions identified as comparable, inevitable and significant coexisting contributors as well as outcomes in chronic infections and tumorigenesis. Besides, iron overload may also develop as an unwanted outcome in certain cancer patients, as a result of symptomatic anaemia treatment owed to irrational iron‐restoration therapies without a prior knowledge of body's iron status with both conditions synergistically acting towards tumour aggravation. The co‐play of iron deficiency and overload along with iron's pro‐tumour and antitumour roles with intersecting mechanisms, thus presents an unpredictable regulatory response loop in a state of malignancy. The relevance of iron's thresholds beyond which it proves to be beneficial against tumorigenesis hence becomes questionable. These factors pose a challenge, over establishing if iron chelation or iron flooding acts as a better approach towards antitumour therapies. This review presents a critical picture of multiple contrasting features of iron's behaviour in cancer, leading towards two conditions lying at opposite ends of a spectrum: iron deficiency and overload in chronic disease conditions including cancer, hence, validating the critical significance of diagnosis of patients' iron status prior to opting for subsequent therapies.
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Affiliation(s)
- Tulika Basak
- Institute for Innovation in Mental and Physical Health and Clinical Translation (IMPACT), School of Medicine, Faculty of Health, Deakin University, Geelong, Victoria, Australia
| | - Rupinder Kaur Kanwar
- Institute for Innovation in Mental and Physical Health and Clinical Translation (IMPACT), School of Medicine, Faculty of Health, Deakin University, Geelong, Victoria, Australia.,Department of Translational Medicine Centre, All India Institute of Medical Sciences (AIIMS) Bhopal, Bhopal, India
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7
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Li Z, Xiao J, Liu M, Cui J, Lian B, Sun Y, Li C. Notch3 regulates ferroptosis via ROS-induced lipid peroxidation in NSCLC cells. FEBS Open Bio 2022; 12:1197-1205. [PMID: 35258176 PMCID: PMC9157401 DOI: 10.1002/2211-5463.13393] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/30/2022] [Accepted: 03/07/2022] [Indexed: 11/10/2022] Open
Abstract
Ferroptosis is type of programmed cell death (PCD), which is known to be involved in certain cancers. Notch3 signaling is reported to be involved in the tumorigenesis of non-small cell lung cancer (NSCLC) and regulates iron metabolism, lipid synthesis and oxidative stress in some tissues. However, whether Notch3 signaling regulates ferroptosis is unclear. In this study, we found that ferroptosis inhibitors, ferrostatin-1 and liproxstatin-1, protected against cell death induced by Notch3 knockdown and that Notch3 knockdown initiated ferroptosis in NSCLC cells by increasing reactive oxygen species (ROS) levels, lipid peroxidation, and Fe2+ levels, accompanied by downregulation of glutathione4 (GPX4) and peroxiredoxin6 (PRDX6). Conversely, Notch3 intracellular domain (NICD3) overexpression suppressed erastin-induced ferroptosis, which was synergistically enhanced by MJ33 in H1299 cells via a decrease in ROS levels and lipid peroxidation, accompanied by upregulation of GPX4 and PRDX6. Moreover, Notch3 knockdown decreased tumorigenesis in vivo with downregulation of GPX4 and PRDX6. In summary, here we have identified Notch3 as a potential negative regulator of ferroptosis in NSCLC.
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Affiliation(s)
- Zhikang Li
- Department of Pharmaceutical science, China Medical University, The Queen's University of Belfast Joint College, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, P.R. China, 110122
| | - JinYang Xiao
- School of life sciences, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, P.R. China, 110122
| | - Mengyu Liu
- School of life sciences, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, P.R. China, 110122
| | - Jiaqi Cui
- School of life sciences, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, P.R. China, 110122
| | - Bowen Lian
- School of life sciences, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, P.R. China, 110122
| | - Yuanlu Sun
- Department of Pharmaceutical science, China Medical University, The Queen's University of Belfast Joint College, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, P.R. China, 110122
| | - Chunyan Li
- Science Experiment Center, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, P.R. China, 110122
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8
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Alnuwaysir RIS, Hoes MF, van Veldhuisen DJ, van der Meer P, Beverborg NG. Iron Deficiency in Heart Failure: Mechanisms and Pathophysiology. J Clin Med 2021; 11:125. [PMID: 35011874 PMCID: PMC8745653 DOI: 10.3390/jcm11010125] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/17/2021] [Accepted: 12/22/2021] [Indexed: 12/15/2022] Open
Abstract
Iron is an essential micronutrient for a myriad of physiological processes in the body beyond erythropoiesis. Iron deficiency (ID) is a common comorbidity in patients with heart failure (HF), with a prevalence reaching up to 59% even in non-anaemic patients. ID impairs exercise capacity, reduces the quality of life, increases hospitalisation rate and mortality risk regardless of anaemia. Intravenously correcting ID has emerged as a promising treatment in HF as it has been shown to alleviate symptoms, improve quality of life and exercise capacity and reduce hospitalisations. However, the pathophysiology of ID in HF remains poorly characterised. Recognition of ID in HF triggered more research with the aim to explain how correcting ID improves HF status as well as the underlying causes of ID in the first place. In the past few years, significant progress has been made in understanding iron homeostasis by characterising the role of the iron-regulating hormone hepcidin, the effects of ID on skeletal and cardiac myocytes, kidneys and the immune system. In this review, we summarise the current knowledge and recent advances in the pathophysiology of ID in heart failure, the deleterious systemic and cellular consequences of ID.
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Affiliation(s)
| | | | | | | | - Niels Grote Beverborg
- Department of Cardiology, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands; (R.I.S.A.); (M.F.H.); (D.J.v.V.); (P.v.d.M.)
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9
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Ying JF, Lu ZB, Fu LQ, Tong Y, Wang Z, Li WF, Mou XZ. The role of iron homeostasis and iron-mediated ROS in cancer. Am J Cancer Res 2021; 11:1895-1912. [PMID: 34094660 PMCID: PMC8167679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 03/01/2021] [Indexed: 06/12/2023] Open
Abstract
As an important trace element, iron plays an essential role in many biology processes like cell proliferation, metabolism, and mitochondrial function. However, the disruption of iron homeostasis tends to cells death and human diseases due to it servers as mediator to promote the production of reactive oxygen species (ROS). In this review, first we introduced the mechanism of complex iron-mediated ROS involved in apoptosis, necroptosis, ferroptosis and pyroptosis. Next, we discussed the controversial role of excess iron and iron deficiency in tumor. Finally, we discussed the anti-cancer effects of iron on both sides, and novel iron-related strategies. This review outlined the mechanisms and regulation of iron homeostasis and iron-mediated ROS in tumors, and discussed the iron-related treatments.
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Affiliation(s)
- Jia-Fu Ying
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
- Clinical Research Institute, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
- Key Laboratory of Molecular Animal Nutrition of The Ministry of Education, Institute of Feed Science, College of Animal Sciences, Zhejiang UniversityHangzhou 310058, Zhejiang Province, P. R. China
| | - Ze-Bei Lu
- Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, P. R. China
| | - Luo-Qin Fu
- Clinical Research Institute, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
| | - Yu Tong
- Clinical Research Institute, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
| | - Zhen Wang
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
| | - Wei-Fen Li
- Key Laboratory of Molecular Animal Nutrition of The Ministry of Education, Institute of Feed Science, College of Animal Sciences, Zhejiang UniversityHangzhou 310058, Zhejiang Province, P. R. China
| | - Xiao-Zhou Mou
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
- Clinical Research Institute, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical CollegeHangzhou 310014, Zhejiang Province, P. R. China
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10
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Yin M, Liu Y, Chen Y. Iron metabolism: an emerging therapeutic target underlying the anti-cancer effect of quercetin. Free Radic Res 2021; 55:296-303. [PMID: 33818251 DOI: 10.1080/10715762.2021.1898604] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Iron, an essential micronutrient for all kinds of cells, is essential for the balance of body internal environment. Notably, cancer cells exhibit a strong dependence on iron and require a large amount of iron for proliferation. A growing number of studies suggested that iron metabolism imbalance and subsequent excess iron accumulation are closely related to the occurrence and progression of cancer. Precisely, excess iron promotes the development of cancer due to the pro-oxidative nature of iron and its damaging effects on DNA. Simultaneously, tumor cells acquire large amounts of iron to maintain rapid growth and proliferation. Therefore, targeting iron metabolism may provide a new way for the treatment of cancer. Quercetin, a natural flavonoid, has long been regarded as potential drug for cancer treatments owing to its anti-inflammatory, antioxidant and anti-tumor effects. It is proven that quercetin possesses a high iron-chelating capacity, depriving cancer cells of iron or altering iron metabolism. Herein, we conduct a review on the mechanisms of iron imbalance in tumors and the role of quercetin in iron chelation, which will provide insight into the potential for quercetin as an anti-cancer drug.
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Affiliation(s)
- Mingming Yin
- College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, PR China
| | - Yongping Liu
- School of Medicine, Hunan University of Chinese Medicine, Changsha, PR China
| | - Yi Chen
- School of Medicine, Hunan University of Chinese Medicine, Changsha, PR China
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11
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Aksan A, Farrag K, Aksan S, Schroeder O, Stein J. Flipside of the Coin: Iron Deficiency and Colorectal Cancer. Front Immunol 2021; 12:635899. [PMID: 33777027 PMCID: PMC7991591 DOI: 10.3389/fimmu.2021.635899] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 02/18/2021] [Indexed: 12/12/2022] Open
Abstract
Iron deficiency, with or without anemia, is the most frequent hematological manifestation in individuals with cancer, and is especially common in patients with colorectal cancer. Iron is a vital micronutrient that plays an essential role in many biological functions, in the context of which it has been found to be intimately linked to cancer biology. To date, however, whereas a large number of studies have comprehensively investigated and reviewed the effects of excess iron on cancer initiation and progression, potential interrelations of iron deficiency with cancer have been largely neglected and are not well-defined. Emerging evidence indicates that reduced iron intake and low systemic iron levels are associated with the pathogenesis of colorectal cancer, suggesting that optimal iron intake must be carefully balanced to avoid both iron deficiency and iron excess. Since iron is vital in the maintenance of immunological functions, insufficient iron availability may enhance oncogenicity by impairing immunosurveillance for neoplastic changes and potentially altering the tumor immune microenvironment. Data from clinical studies support these concepts, showing that iron deficiency is associated with inferior outcomes and reduced response to therapy in patients with colorectal cancer. Here, we elucidate cancer-related effects of iron deficiency, examine preclinical and clinical evidence of its role in tumorigenesis, cancer progression and treatment response. and highlight the importance of adequate iron supplementation to limit these outcomes.
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Affiliation(s)
- Aysegül Aksan
- Institute of Nutritional Science, Justus-Liebig University, Giessen, Germany.,Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany.,Interdisziplinäres Crohn Colitis Centrum, Rhein-Main, Frankfurt, Germany
| | - Karima Farrag
- Interdisziplinäres Crohn Colitis Centrum, Rhein-Main, Frankfurt, Germany.,DGD Kliniken Sachsenhausen, Frankfurt, Germany
| | - Sami Aksan
- Interdisziplinäres Crohn Colitis Centrum, Rhein-Main, Frankfurt, Germany.,DGD Kliniken Sachsenhausen, Frankfurt, Germany
| | - Oliver Schroeder
- Interdisziplinäres Crohn Colitis Centrum, Rhein-Main, Frankfurt, Germany.,DGD Kliniken Sachsenhausen, Frankfurt, Germany
| | - Jürgen Stein
- Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany.,Interdisziplinäres Crohn Colitis Centrum, Rhein-Main, Frankfurt, Germany.,DGD Kliniken Sachsenhausen, Frankfurt, Germany
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12
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Orzechowska M, Anusewicz D, Bednarek AK. Functional Gene Expression Differentiation of the Notch Signaling Pathway in Female Reproductive Tract Tissues-A Comprehensive Review With Analysis. Front Cell Dev Biol 2021; 8:592616. [PMID: 33384996 PMCID: PMC7770115 DOI: 10.3389/fcell.2020.592616] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 11/11/2020] [Indexed: 12/13/2022] Open
Abstract
The Notch pathway involves evolutionarily conserved signaling regulating the development of the female tract organs such as breast, ovary, cervix, and uterine endometrium. A great number of studies revealed Notch aberrancies in association with their carcinogenesis and disease progression, the management of which is still challenging. The present study is a comprehensive review of the available literature on Notch signaling during the normal development and carcinogenesis of the female tract organs. The review has been enriched with our analyses of the TCGA data including breast, cervical, ovarian, and endometrial carcinomas concerning the effects of Notch signaling at two levels: the core components and downstream effectors, hence filling the lack of global overview of Notch-driven carcinogenesis and disease progression. Phenotype heterogeneity regarding Notch signaling was projected in two uniform manifold approximation and projection algorithm dimensions, preceded by the principal component analysis step reducing the data burden. Additionally, overall and disease-free survival analyses were performed with the optimal cutpoint determination by Evaluate Cutpoints software to establish the character of particular Notch components in tumorigenesis. In addition to the review, we demonstrated separate models of the examined cancers of the Notch pathway and its targets, although expression profiles of all normal tissues were much more similar to each other than to its cancerous compartments. Such Notch-driven cancerous differentiation resulted in a case of opposite association with DFS and OS. As a consequence, target genes also show very distinct profiles including genes associated with cell proliferation and differentiation, energy metabolism, or the EMT. In conclusion, the observed Notch associations with the female tract malignancies resulted from differential expression of target genes. This may influence a future analysis to search for new therapeutic targets based on specific Notch pathway profiles.
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Affiliation(s)
| | - Dorota Anusewicz
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
| | - Andrzej K Bednarek
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
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13
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Li Z, Chen L, Chen C, Zhou Y, Hu D, Yang J, Chen Y, Zhuo W, Mao M, Zhang X, Xu L, Wang L, Zhou J. Targeting ferroptosis in breast cancer. Biomark Res 2020; 8:58. [PMID: 33292585 PMCID: PMC7643412 DOI: 10.1186/s40364-020-00230-3] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 09/23/2020] [Indexed: 02/06/2023] Open
Abstract
Ferroptosis is a recently discovered distinct type of regulated cell death caused by the accumulation of lipid-based ROS. Metabolism and expression of specific genes affect the occurrence of ferroptosis, making it a promising therapeutic target to manage cancer. Here, we describe the current status of ferroptosis studies in breast cancer and trace the key regulators of ferroptosis back to previous studies. We also compare ferroptosis to common regulated cell death patterns and discuss the sensitivity to ferroptosis in different subtypes of breast cancer. We propose that viewing ferroptosis-related studies from a historical angle will accelerate the development of ferroptosis-based biomarkers and therapeutic strategies in breast cancer.
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Affiliation(s)
- Zhaoqing Li
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), 2nd Affiliated Hospital, School of Medicine, Zhejiang University, 310009 Hangzhou, Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Lini Chen
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Cong Chen
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Yulu Zhou
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Dengdi Hu
- Cixi People’s Hospital Medical and Health Group, 315300 Ningbo, Zhejiang China
| | - Jingjing Yang
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Yongxia Chen
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Wenying Zhuo
- Cixi People’s Hospital Medical and Health Group, 315300 Ningbo, Zhejiang China
| | - Misha Mao
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Xun Zhang
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Ling Xu
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Linbo Wang
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
| | - Jichun Zhou
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310000 Zhejiang China
- Biomedical Research Center and Key Laboratory of Biotherapy of Zhejiang Province, 310000 Hangzhou, Zhejiang China
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14
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Serra M, Columbano A, Ammarah U, Mazzone M, Menga A. Understanding Metal Dynamics Between Cancer Cells and Macrophages: Competition or Synergism? Front Oncol 2020; 10:646. [PMID: 32426284 PMCID: PMC7203474 DOI: 10.3389/fonc.2020.00646] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 04/07/2020] [Indexed: 12/13/2022] Open
Abstract
Metal ions, such as selenium, copper, zinc, and iron are naturally present in the environment (air, drinking water, and food) and are vital for cellular functions at chemical, molecular, and biological levels. These trace elements are involved in various biochemical reactions by acting as cofactors for many enzymes and control important biological processes by binding to the receptors and transcription factors. Moreover, they are essential for the stabilization of the cellular structures and for the maintenance of genome stability. A body of preclinical and clinical evidence indicates that dysregulation of metal homeostasis, both at intracellular and tissue level, contributes to the pathogenesis of many different types of cancer. These trace minerals play a crucial role in preventing or accelerating neoplastic cell transformation and in modulating the inflammatory and pro-tumorigenic response in immune cells, such as macrophages, by controlling a plethora of metabolic reactions. In this context, macrophages and cancer cells interact in different manners and some of these interactions are modulated by availability of metals. The current review discusses the new findings and focuses on the involvement of these micronutrients in metabolic and cellular signaling mechanisms that influence macrophage functions, onset of cancer and its progression. An improved understanding of "metallic" cross-talk between macrophages and cancer cells may pave the way for innovative pharmaceutical or dietary interventions in order to restore the balance of these trace elements and also strengthen the chemotherapeutic treatment.
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Affiliation(s)
- Marina Serra
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, Leuven, Belgium
| | - Amedeo Columbano
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Ummi Ammarah
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, Leuven, Belgium
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center – MBC, University of Torino, Turin, Italy
| | - Massimiliano Mazzone
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, Leuven, Belgium
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center – MBC, University of Torino, Turin, Italy
| | - Alessio Menga
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology (CCB), VIB, Leuven, Belgium
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center – MBC, University of Torino, Turin, Italy
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15
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Fan H, Su Y, Duan C, Zhao Q, Wang X, Zhu S, Zhao W, Jin M, Ma X. Iron deficiency in children at the time of initial neuroblastoma diagnosis. Pediatr Investig 2020; 4:17-22. [PMID: 32851337 PMCID: PMC7331340 DOI: 10.1002/ped4.12156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 07/23/2019] [Indexed: 11/25/2022] Open
Abstract
IMPORTANCE There is a high incidence of iron deficiency in children worldwide. Notably, however, while iron deficiency is the most common cause of anemia, little is known about the prevalence and different types of iron deficiency in neuroblastoma patients. OBJECTIVE The aim of the present study was to investigate the prevalence of iron deficiency in patients newly diagnosed with neuroblastoma. METHODS A total of 195 newly diagnosed neuroblastoma patients from November 2015 to January 2018 were analyzed retrospectively. The survival analysis was estimated by the Kaplan-Meier method. RESULTS Of the 195 neuroblastoma patients included in the study, 121 (62.1%) had iron deficiency, 55 (28.2%) had absolute iron deficiency, and 66 (33.9%) had functional iron deficiency. Being aged ≥ 18 months, tumor originating in the abdomen, International Neuroblastoma Risk Group Staging System M, high-risk neuroblastoma, lactate dehydrogenase ≥ 1500 U/L, neuron-specific enolase ≥ 100 U/L, unfavorable histologic category, MYCN amplification, chromosome 1p loss, and bone marrow metastasis were associated with significantly higher rates of functional iron deficiency (P < 0.05). INTERPRETATION Functional iron deficiency at the time of initial neuroblastoma diagnosis predicted lower event-free survival. Long-term effects of iron supplementation in neuroblastoma patients with different types of iron deficiency need to be further studied.
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Affiliation(s)
- Hongjun Fan
- Beijing Key Laboratory of Pediatric Hematology OncologyNational Discipline of PediatricsMinistry of EducationMOE Key Laboratory of Major Diseases in ChildrenHematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Yan Su
- Beijing Key Laboratory of Pediatric Hematology OncologyNational Discipline of PediatricsMinistry of EducationMOE Key Laboratory of Major Diseases in ChildrenHematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Chao Duan
- Beijing Key Laboratory of Pediatric Hematology OncologyNational Discipline of PediatricsMinistry of EducationMOE Key Laboratory of Major Diseases in ChildrenHematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Qian Zhao
- Beijing Key Laboratory of Pediatric Hematology OncologyNational Discipline of PediatricsMinistry of EducationMOE Key Laboratory of Major Diseases in ChildrenHematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Xisi Wang
- Beijing Key Laboratory of Pediatric Hematology OncologyNational Discipline of PediatricsMinistry of EducationMOE Key Laboratory of Major Diseases in ChildrenHematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Shuai Zhu
- Beijing Key Laboratory of Pediatric Hematology OncologyNational Discipline of PediatricsMinistry of EducationMOE Key Laboratory of Major Diseases in ChildrenHematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Wen Zhao
- Beijing Key Laboratory of Pediatric Hematology OncologyNational Discipline of PediatricsMinistry of EducationMOE Key Laboratory of Major Diseases in ChildrenHematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Mei Jin
- Beijing Key Laboratory of Pediatric Hematology OncologyNational Discipline of PediatricsMinistry of EducationMOE Key Laboratory of Major Diseases in ChildrenHematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
| | - Xiaoli Ma
- Beijing Key Laboratory of Pediatric Hematology OncologyNational Discipline of PediatricsMinistry of EducationMOE Key Laboratory of Major Diseases in ChildrenHematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityNational Center for Children’s HealthBeijingChina
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16
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Sornjai W, Nguyen Van Long F, Pion N, Pasquer A, Saurin JC, Marcel V, Diaz JJ, Mertani HC, Smith DR. Iron and hepcidin mediate human colorectal cancer cell growth. Chem Biol Interact 2020; 319:109021. [PMID: 32092301 DOI: 10.1016/j.cbi.2020.109021] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 01/24/2020] [Accepted: 02/20/2020] [Indexed: 12/20/2022]
Abstract
High dietary iron intake is a risk factor for the development of colorectal cancer. However, how iron subsequently impacts the proliferation of colorectal cancer cells remains unclear. This study determined the expression of six iron regulatory genes in twenty-one human colorectal cancer (CRC) biopsies and matched normal colonic tissue. The results show that only hepcidin and ferritin heavy chain expression were increased in CRC biopsies as compared to matched normal tissues. Four established human CRC cell lines, HT-29, HCT-116, SW-620 and SW-480 were subsequently examined for their growth in response to increasing concentrations of iron, and iron depletion. Real time cell growth assay showed a significant inhibitory effect of acute iron loading in HCT-116 cells (IC50 = 258.25 μM at 72 h), and no significant effects in other cell types. However, ten week treatment with iron significantly reduced HT-29 and SW-620 cell growth, whereas no effect was seen in HCT-116 and SW-480 cells. Intracellular labile iron depletion induced the complete growth arrest and detachment of all of the CRC cell types except for the SW-620 cell line which was not affected in its growth. Treatment of starved CRC cells with hepcidin, the major regulator of iron metabolism, induced a significant stimulation of HT-29 cell growth but did not affect the growth of the other cell types. Collectively these results show that iron is central to CRC cell growth in a manner that is not identical between acute and chronic loading, and that is specific to the CRC cell type.
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Affiliation(s)
- Wannapa Sornjai
- Institute of Molecular Biosciences, Mahidol University, 25/25 Phuttamonthon Sai 4, Salaya, Nakon Pathom, 73170, Thailand
| | - Flora Nguyen Van Long
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052-CNRS 5286, Centre Léon Bérard, Université Claude Bernard Lyon I, Université de Lyon, Lyon, 69008, France
| | - Nathalie Pion
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052-CNRS 5286, Centre Léon Bérard, Université Claude Bernard Lyon I, Université de Lyon, Lyon, 69008, France
| | - Arnaud Pasquer
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052-CNRS 5286, Centre Léon Bérard, Université Claude Bernard Lyon I, Université de Lyon, Lyon, 69008, France
| | - Jean-Christophe Saurin
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052-CNRS 5286, Centre Léon Bérard, Université Claude Bernard Lyon I, Université de Lyon, Lyon, 69008, France
| | - Virginie Marcel
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052-CNRS 5286, Centre Léon Bérard, Université Claude Bernard Lyon I, Université de Lyon, Lyon, 69008, France
| | - Jean Jacques Diaz
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052-CNRS 5286, Centre Léon Bérard, Université Claude Bernard Lyon I, Université de Lyon, Lyon, 69008, France
| | - Hichem C Mertani
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052-CNRS 5286, Centre Léon Bérard, Université Claude Bernard Lyon I, Université de Lyon, Lyon, 69008, France.
| | - Duncan R Smith
- Institute of Molecular Biosciences, Mahidol University, 25/25 Phuttamonthon Sai 4, Salaya, Nakon Pathom, 73170, Thailand.
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17
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Zhang Y, Xie ZY, Guo XT, Xiao XH, Xiong LX. Notch and breast cancer metastasis: Current knowledge, new sights and targeted therapy. Oncol Lett 2019; 18:2743-2755. [PMID: 31452752 PMCID: PMC6704289 DOI: 10.3892/ol.2019.10653] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 06/21/2019] [Indexed: 02/07/2023] Open
Abstract
Breast cancer is the most common type of invasive cancer in females and metastasis is one of the major causes of breast cancer-associated mortality. Following detachment from the primary site, disseminated tumor cells (DTCs) enter the bloodstream and establish secondary colonies during the metastatic process. An increasing amount of studies have elucidated the importance of Notch signaling in breast cancer metastasis; therefore, the present review focuses on the mechanisms by which Notch contributes to the occurrence of breast cancer DTCs, increases their motility, establishes interactions with the tumor microenvironment, protects DTCs from host surveillance and finally facilitates secondary colonization. Identification of the underlying mechanisms of Notch-associated breast cancer metastasis will provide additional insights that may contribute towards the development of novel Notch-targeted therapeutic strategies, which may aid in reducing metastasis, culminating in an improved patient prognosis.
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Affiliation(s)
- Yu Zhang
- Department of Pathophysiology, Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Zi-Yan Xie
- Department of Pathophysiology, Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xuan-Tong Guo
- Department of Pathophysiology, Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xing-Hua Xiao
- Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Li-Xia Xiong
- Department of Pathophysiology, Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- Jiangxi Province Key Laboratory of Tumor Pathogenesis and Molecular Pathology, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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18
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Mehta KJ, Farnaud SJ, Sharp PA. Iron and liver fibrosis: Mechanistic and clinical aspects. World J Gastroenterol 2019; 25:521-538. [PMID: 30774269 PMCID: PMC6371002 DOI: 10.3748/wjg.v25.i5.521] [Citation(s) in RCA: 182] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 01/02/2019] [Accepted: 01/10/2019] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is characterised by excessive deposition of extracellular matrix that interrupts normal liver functionality. It is a pathological stage in several untreated chronic liver diseases such as the iron overload syndrome hereditary haemochromatosis, viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and diabetes. Interestingly, regardless of the aetiology, iron-loading is frequently observed in chronic liver diseases. Excess iron can feed the Fenton reaction to generate unquenchable amounts of free radicals that cause grave cellular and tissue damage and thereby contribute to fibrosis. Moreover, excess iron can induce fibrosis-promoting signals in the parenchymal and non-parenchymal cells, which accelerate disease progression and exacerbate liver pathology. Fibrosis regression is achievable following treatment, but if untreated or unsuccessful, it can progress to the irreversible cirrhotic stage leading to organ failure and hepatocellular carcinoma, where resection or transplantation remain the only curative options. Therefore, understanding the role of iron in liver fibrosis is extremely essential as it can help in formulating iron-related diagnostic, prognostic and treatment strategies. These can be implemented in isolation or in combination with the current approaches to prepone detection, and halt or decelerate fibrosis progression before it reaches the irreparable stage. Thus, this review narrates the role of iron in liver fibrosis. It examines the underlying mechanisms by which excess iron can facilitate fibrotic responses. It describes the role of iron in various clinical pathologies and lastly, highlights the significance and potential of iron-related proteins in the diagnosis and therapeutics of liver fibrosis.
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Affiliation(s)
- Kosha J Mehta
- School of Population Health and Environmental Sciences, Faculty of Life Sciences and Medicine, King’s College London, London SE1 1UL, United Kingdom
- Division of Human Sciences, School of Applied Sciences, London South Bank University, London SE1 0AA, United Kingdom
| | - Sebastien Je Farnaud
- Faculty Research Centre for Sport, Exercise and Life Sciences, Coventry University, Coventry CV1 2DS, United Kingdom
| | - Paul A Sharp
- Department of Nutritional Sciences, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London SE1 9NH, United Kingdom
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19
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Jung M, Mertens C, Tomat E, Brüne B. Iron as a Central Player and Promising Target in Cancer Progression. Int J Mol Sci 2019; 20:ijms20020273. [PMID: 30641920 PMCID: PMC6359419 DOI: 10.3390/ijms20020273] [Citation(s) in RCA: 167] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 01/08/2019] [Accepted: 01/09/2019] [Indexed: 02/07/2023] Open
Abstract
Iron is an essential element for virtually all organisms. On the one hand, it facilitates cell proliferation and growth. On the other hand, iron may be detrimental due to its redox abilities, thereby contributing to free radical formation, which in turn may provoke oxidative stress and DNA damage. Iron also plays a crucial role in tumor progression and metastasis due to its major function in tumor cell survival and reprogramming of the tumor microenvironment. Therefore, pathways of iron acquisition, export, and storage are often perturbed in cancers, suggesting that targeting iron metabolic pathways might represent opportunities towards innovative approaches in cancer treatment. Recent evidence points to a crucial role of tumor-associated macrophages (TAMs) as a source of iron within the tumor microenvironment, implying that specifically targeting the TAM iron pool might add to the efficacy of tumor therapy. Here, we provide a brief summary of tumor cell iron metabolism and updated molecular mechanisms that regulate cellular and systemic iron homeostasis with regard to the development of cancer. Since iron adds to shaping major hallmarks of cancer, we emphasize innovative therapeutic strategies to address the iron pool of tumor cells or cells of the tumor microenvironment for the treatment of cancer.
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Affiliation(s)
- Michaela Jung
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
| | - Christina Mertens
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
| | - Elisa Tomat
- Department of Chemistry and Biochemistry, University of Arizona, 1306 E. University Blvd., Tucson, AZ 85721-0041, USA.
| | - Bernhard Brüne
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
- German Cancer Consortium (DKTK), Partner Site Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
- Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology, 60596 Frankfurt, Germany.
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20
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Pfeifhofer-Obermair C, Tymoszuk P, Petzer V, Weiss G, Nairz M. Iron in the Tumor Microenvironment-Connecting the Dots. Front Oncol 2018; 8:549. [PMID: 30534534 PMCID: PMC6275298 DOI: 10.3389/fonc.2018.00549] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 11/06/2018] [Indexed: 12/18/2022] Open
Abstract
Iron metabolism and tumor biology are intimately linked. Iron facilitates the production of oxygen radicals, which may either result in iron-induced cell death, ferroptosis, or contribute to mutagenicity and malignant transformation. Once transformed, malignant cells require high amounts of iron for proliferation. In addition, iron has multiple regulatory effects on the immune system, thus affecting tumor surveillance by immune cells. For these reasons, inconsiderate iron supplementation in cancer patients has the potential of worsening disease course and outcome. On the other hand, chronic immune activation in the setting of malignancy alters systemic iron homeostasis and directs iron fluxes into myeloid cells. While this response aims at withdrawing iron from tumor cells, it may impair the effector functions of tumor-associated macrophages and will result in iron-restricted erythropoiesis and the development of anemia, subsequently. This review summarizes our current knowledge of the interconnections of iron homeostasis with cancer biology, discusses current clinical controversies in the treatment of anemia of cancer and focuses on the potential roles of iron in the solid tumor microenvironment, also speculating on yet unknown molecular mechanisms.
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Affiliation(s)
- Christa Pfeifhofer-Obermair
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria
| | - Piotr Tymoszuk
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria
| | - Verena Petzer
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria.,Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria
| | - Manfred Nairz
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University of Innsbruck, Innsbruck, Austria
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21
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Zohora F, Bidad K, Pourpak Z, Moin M. Biological and Immunological Aspects of Iron Deficiency Anemia in Cancer Development: A Narrative Review. Nutr Cancer 2018; 70:546-556. [PMID: 29697284 DOI: 10.1080/01635581.2018.1460685] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Iron Deficiency Anemia (IDA) is a universal health problem and a risk factor for the development of cancer. IDA changes the microenvironment of the human body by affecting both the biological and immunological systems. It increases DNA damage and genomic instability by different mechanisms. IDA is one of the leading causes of the imbalance between different antioxidant enzymes as well as enzymes involved in DNA damage and DNA repair systems of the body. It can affect the biogenesis/expression of microRNAs. IDA interrupts the oxidative phosphorylation energy metabolism and intestinal Cytochrome-P450 systems. It also disturbs multicellular signaling pathways involved in cell survival and helps in tumor angiogenesis. Moreover, IDA is also responsible for the functional deterioration of innate and adaptive immune systems that lead to immunological dysfunctions against invading pathogens. Genomic instability and immunological dysfunctions are the hallmarks of cancer development. In this review, we will review the evidence linking IDA to increased cancer risk.
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Affiliation(s)
- Fatema Zohora
- a Immunology, Asthma & Allergy Research Institute (IAARI), Tehran University of Medical Sciences (TUMS) , Tehran , Iran
| | - Katayoon Bidad
- a Immunology, Asthma & Allergy Research Institute (IAARI), Tehran University of Medical Sciences (TUMS) , Tehran , Iran
| | - Zahra Pourpak
- a Immunology, Asthma & Allergy Research Institute (IAARI), Tehran University of Medical Sciences (TUMS) , Tehran , Iran
| | - Mostafa Moin
- a Immunology, Asthma & Allergy Research Institute (IAARI), Tehran University of Medical Sciences (TUMS) , Tehran , Iran
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Rajizadeh A, Mozaffari-Khosravi H, Zavar-reza J, Shiryazdi SM. Comparison of hematological parameters, iron levels, and oxidative stress in women with and without breast cancer: A case- control study. Med J Islam Repub Iran 2017; 31:114. [PMID: 29951415 PMCID: PMC6014764 DOI: 10.14196/mjiri.31.114] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Indexed: 01/08/2023] Open
Abstract
Background: Iron is one of the nutrients that has recently received considerable attention because of its dual role in the incidence of breast cancer. The present study aimed at comparing hematological parameters, iron levels, and oxidative stress in women with and without breast cancer. Methods: The participants in this case-control study were 55 women, of whom 26 were new cases of breast cancer (confirmed by biopsy) as the case, and 29 without cancer (confirmed by mammography) as the control group. All participants underwent blood testing for complete blood count (CBC (free iron, ferritin, total iron binding capacity) TIBC (2, 2-diphenyl-1-picrylhydrazyl (DPPH), and Malondialdehyde (MDA). Results: The mean±SD age of the participants was 44.25±9.82 years, and there was no significant difference between groups. Also, no statistically significant difference was found between the 2 groups in variables, except the mean corpuscular volume of red cells (MCV), mean corpuscular hemoglobin concentration (MCHC), and mean cell hemoglobin (MCH). The use of iron supplements was significantly higher in the control than in the case group (p= 0. 01), with an odds ratio of 0.19% (95% CI: 0.45-0.7). The mean serum DPPH was significantly higher in the control than in the case group (p= 0. 006), but comparison of serum MDA showed no significant difference between the 2 groups. Conclusion: Iron deficiency anemia was greater in patients with breast cancer than in those without it. Moreover, iron supplementation appears to have a protective effect against breast cancer incidence. In addition, serum DPPH, as a total antioxidant index, was significantly higher in the control group.
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Affiliation(s)
- Afsaneh Rajizadeh
- Nutrition and Food Security Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Hassan Mozaffari-Khosravi
- Department of Nutrition, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
- Yazd Diabetic Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Javad Zavar-reza
- Department of Biochemistry, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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Hammerbeck H. Iron homeostasis: complex effects beyond anaemia. Anaesthesia 2017; 72:1285-1286. [DOI: 10.1111/anae.14045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Intracellular Iron Chelation Modulates the Macrophage Iron Phenotype with Consequences on Tumor Progression. PLoS One 2016; 11:e0166164. [PMID: 27806101 PMCID: PMC5091876 DOI: 10.1371/journal.pone.0166164] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 10/23/2016] [Indexed: 12/23/2022] Open
Abstract
A growing body of evidence suggests that macrophage polarization dictates the expression of iron-regulated genes. Polarization towards iron sequestration depletes the microenvironment, whereby extracellular pathogen growth is limited and inflammation is fostered. In contrast, iron release contributes to cell proliferation, which is important for tissue regeneration. Moreover, macrophages constitute a major component of the infiltrates in most solid tumors. Considering the pivotal role of macrophages for iron homeostasis and their presence in association with poor clinical prognosis in tumors, we approached the possibility to target macrophages with intracellular iron chelators. Analyzing the expression of iron-regulated genes at mRNA and protein level in primary human macrophages, we found that the iron-release phenotype is a characteristic of polarized macrophages that, in turn, stimulate tumor cell growth and progression. The application of the intracellular iron chelator (TC3-S)2 shifted the macrophage phenotype from iron release towards sequestration, as determined by the iron-gene profile and atomic absorption spectroscopy (AAS). Moreover, whereas the addition of macrophage supernatants to tumor cells induced tumor growth and metastatic behavior, the supernatant of chelator-treated macrophages reversed this effect. Iron chelators demonstrated potent anti-neoplastic properties in a number of cancers, both in cell culture and in clinical trials. Our results suggest that iron chelation could affect not only cancer cells but also the tumor microenvironment by altering the iron-release phenotype of tumor-associated macrophages (TAMs). The study of iron chelators in conjunction with the effect of TAMs on tumor growth could lead to an improved understanding of the role of iron in cancer biology and to novel therapeutic avenues for iron chelation approaches.
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Brigham EP, McCormack MC, Takemoto CM, Matsui EC. Iron status is associated with asthma and lung function in US women. PLoS One 2015; 10:e0117545. [PMID: 25689633 PMCID: PMC4331366 DOI: 10.1371/journal.pone.0117545] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 12/28/2014] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Asthma and iron deficiency are common conditions. Whether iron status affects the risk of asthma is unclear. OBJECTIVE To determine the relationship between iron status and asthma, lung function, and pulmonary inflammation. METHODS Relationships between measures of iron status (serum ferritin, serum soluble transferrin receptor (sTfR), and sTfR/log10ferritin (sTfR-F Index)) and asthma, lung function, and pulmonary inflammation were examined in women 20-49 years in the National Health and Nutrition Examination Survey. Logistic, linear, and quadratic regression models accounting for the survey design of NHANES were used to evaluate associations between iron status and asthma-related outcomes and were adjusted for race/ethnicity, age, smoking status, income, and BMI. RESULTS Approximately 16% reported a lifetime history of asthma, 9% reported current asthma, and 5% reported a recent asthma episode/attack (n = 2906). Increased ferritin (iron stores) was associated with decreased odds of lifetime asthma, current asthma, and asthma attacks/episodes in the range of ferritin linearly correlated with iron stores (20-300ng/ml). The highest quintile of ferritin (>76 ng/ml) was also associated with a decreased odds of asthma. Ferritin levels were not associated with FEV1. Increased values of the sTfR-F Index and sTfR, indicating lower body iron and higher tissue iron need, respectively, were associated with decreased FEV1, but neither was associated with asthma. None of the iron indices were associated with FeNO. CONCLUSION In US women, higher iron stores were inversely associated with asthma and lower body iron and higher tissue iron need were associated with lower lung function. Together, these findings suggest that iron status may play a role in asthma and lung function in US women.
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Affiliation(s)
- Emily P. Brigham
- Johns Hopkins University School of Medicine, Division of Pulmonary and Critical Care Medicine, Baltimore, Maryland, United States of America
| | - Meredith C. McCormack
- Johns Hopkins University School of Medicine, Division of Pulmonary and Critical Care Medicine, Baltimore, Maryland, United States of America
- Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America
| | - Clifford M. Takemoto
- Johns Hopkins University School of Medicine, Division of Pediatric Hematology, Baltimore, Maryland, United States of America
| | - Elizabeth C. Matsui
- Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, United States of America
- Johns Hopkins University School of Medicine, Division of Pediatric Allergy and Immunology, Baltimore, Maryland, United States of America
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Abstract
Iron is essential for the growth and proliferation of cells, as well as for many biological processes that are important for the maintenance and survival of the human body. However, excess iron is associated with the development of cancer and other pathological conditions, due in part to the pro-oxidative nature of iron and its damaging effects on DNA. Current studies suggest that iron depletion may be beneficial for patients that have diseases associated with iron overload or other iron metabolism disorders that may increase the risk for cancer. On the other hand, studies suggest that cancer cells are more vulnerable to the effects of iron depletion and oxidative stress in comparison to normal cells. Therefore, cancer patients might benefit from treatments that alter both iron metabolism and oxidative stress. This review highlights the pro-oxidant effects of iron, the relationship between iron and cancer development, the vulnerabilities of the iron-dependent cancer phenotype, and how these characteristics may be exploited to prevent or treat cancer.
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Affiliation(s)
- Laura M Bystrom
- Department of Pediatrics-Hematology/Oncology, Weill Cornell Medical College, New York, NY 10021, USA.
| | - Stefano Rivella
- Department of Pediatrics-Hematology/Oncology, Weill Cornell Medical College, New York, NY 10021, USA; Department of Cell and Development Biology, Weill Cornell Medical College, New York, NY 10021, USA.
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Ogawa C, Tsuchiya K, Kanda F, Maeda T. Low levels of serum ferritin lead to adequate hemoglobin levels and good survival in hemodialysis patients. Am J Nephrol 2015; 40:561-70. [PMID: 25592750 DOI: 10.1159/000370317] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Accepted: 11/27/2014] [Indexed: 11/19/2022]
Abstract
BACKGROUND The optimal level of serum ferritin (s-ft) for anemia control and good survival in hemodialysis (HD) patients remains unclear. A 10-year survey was performed to clarify the appropriate quantities of s-ft and investigate the relationships among s-ft, transferrin saturation (TSAT), and mortality in HD patients. METHODS HD outpatients (n = 125) treated with erythropoiesis-stimulating agents (ESA) were followed for 10 years. The ESA and low-dose iron supplement dosages were adjusted to maintain the hemoglobin (Hb) at 10-11 g/dl, according to Japanese guidelines. The Kaplan-Meier method, log-rank tests, and the Cox proportional hazards model were used for performing the statistical analyses. The interactions among the Hb, s-ft, and TSAT were analyzed using a multiple linear regression model. Patients with TSAT ≥20% were classified according to the s-ft cutoff values: group 1 (s-ft <30 ng/ml); group 2 (s-ft 30-80 ng/ml); group 3 (s-ft >80 ng/ml); TSAT <20% was a predictor of poor outcome. RESULTS The survival rate in group 2 was significantly higher than that in other groups (p = 0.013), and the Cox proportional hazards model analysis showed a good effect of low levels of s-ft on patients' survival. The multiple linear regression model showed a strong effect of s-ft on the Hb (log [s-ft], β-coefficient -0.45: 95% confidence interval -0.65 to -0.26, p < 0.001). CONCLUSION This study revealed that low levels of s-ft have a beneficial effect on the outcome of HD patients receiving ESA. Thus, the optimal s-ft level might be lower than that established previously for these patients.
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Affiliation(s)
- Chie Ogawa
- Maeda Institute of Renal Research, Division of Nephrology, Department of Internal Medicine, Department of Medicine, Kidney Center, Kawasaki City, Japan
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Kamdje AHN, Etet PFS, Vecchio L, Tagne RS, Amvene JM, Muller JM, Krampera M, Lukong KE. New targeted therapies for breast cancer: A focus on tumor microenvironmental signals and chemoresistant breast cancers. World J Clin Cases 2014; 2:769-86. [PMID: 25516852 PMCID: PMC4266825 DOI: 10.12998/wjcc.v2.i12.769] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 07/12/2014] [Accepted: 09/23/2014] [Indexed: 02/05/2023] Open
Abstract
Breast cancer is the most frequent female malignancy worldwide. Current strategies in breast cancer therapy, including classical chemotherapy, hormone therapy, and targeted therapies, are usually associated with chemoresistance and serious adverse effects. Advances in our understanding of changes affecting the interactome in advanced and chemoresistant breast tumors have provided novel therapeutic targets, including, cyclin dependent kinases, mammalian target of rapamycin, Notch, Wnt and Shh. Inhibitors of these molecules recently entered clinical trials in mono- and combination therapy in metastatic and chemo-resistant breast cancers. Anticancer epigenetic drugs, mainly histone deacetylase inhibitors and DNA methyltransferase inhibitors, also entered clinical trials. Because of the complexity and heterogeneity of breast cancer, the future in therapy lies in the application of individualized tailored regimens. Emerging therapeutic targets and the implications for personalized-based therapy development in breast cancer are herein discussed.
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Jung M, Mertens C, Brüne B. Macrophage iron homeostasis and polarization in the context of cancer. Immunobiology 2014; 220:295-304. [PMID: 25260218 DOI: 10.1016/j.imbio.2014.09.011] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 08/07/2014] [Accepted: 09/05/2014] [Indexed: 12/28/2022]
Abstract
Macrophages are central in regulating iron homeostasis, which is tightly linked to their versatile role during innate immunity. They sequester iron by phagocytosis of senescent erythrocytes and represent a major source of available iron in the body. Macrophage iron homeostasis is coupled to the functional heterogeneity and plasticity of these cells, with their extreme roles during inflammation, immune modulation, and resolution of inflammation. It is now appreciated that the macrophage polarization process dictates expression profiles of genes involved in iron metabolism. Therefore, macrophages have evolved a multitude of mechanisms to sequester, transport, store, and release iron. A new, enigmatic protein entering the iron scene and affecting the macrophage phenotype is lipocalin-2. Iron sequestration in macrophages depletes the microenvironment, thereby limiting extracellular pathogen or tumor growth, while fostering inflammation. In contrast, iron release from macrophages contributes to bystander cell proliferation, which is important for tissue regeneration and repair. This dichotomy is also reflected by the dual role of lipocalin-2 in macrophages. Unfortunately, the iron release macrophage phenotype is also a characteristic of tumor-associated macrophages and stimulates tumor cell survival and growth. Iron sequestration versus its release is now appreciated to be associated with the macrophage polarization program and can be used to explain a number of biological functions attributed to distinct macrophage phenotypes. Here we discuss macrophage iron homeostasis with a special focus on lipocalin-2 related to the formation and function of tumor-associated macrophages.
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Affiliation(s)
- Michaela Jung
- Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany
| | - Christina Mertens
- Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany
| | - Bernhard Brüne
- Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
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30
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Iron homeostasis in breast cancer. Cancer Lett 2014; 347:1-14. [DOI: 10.1016/j.canlet.2014.01.029] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/16/2013] [Accepted: 01/24/2014] [Indexed: 02/08/2023]
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