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1
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Dharmasivam M, Zhang S, Zhao X, Richardson V, Wijesinghe TP, Suleymanoglu M, Gholam Azad M, Bernhardt PV, Kaya B, Richardson DR. Advantages of Novel Anti-cancer Selenosemicarbazones: Preferential Reactivity of Their Fe(III), Cu(II), and Zn(II) Complexes with Key Physiological Reductants/Ligands Versus Isosteric Thiosemicarbazones. J Med Chem 2025; 68:9594-9622. [PMID: 40265585 DOI: 10.1021/acs.jmedchem.5c00374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
Fe(III) complexes of clinically trialed thiosemicarbazones demonstrate deleterious oxy-myoglobin and oxy-hemoglobin oxidation. Therefore, the PPP4pSe selenosemicarbazone analogues were designed with several PPP4pSe Fe(III) complexes completely preventing deleterious oxy-myoglobin oxidation. This was ascribed to the decreased potentials of their Fe(III) complexes and steric hindrance effects. The Fe(III), Cu(II), and Zn(II) complexes of PPP4pSe demonstrated greater reactivity with physiological reductants/ligands (glutathione, l-cysteine, or l-ascorbate), than respective complexes of the isosteric thiosemicarbazone, PPP4pT. Considering this: (1) [Fe(PPP4pSe)2]+ demonstrated increased reduction relative to [Fe(PPP4pT)2]+ with glutathione and l-cysteine, while l-ascorbate led to comparable reduction; (2) glutathione led to complete dissociation of [Zn(PPP4pSe)2], while incomplete dissociation of [Zn(PPP4pT)2] occurred; and (3) [Cu(PPP4pSe)Cl] demonstrated complete coordinate sphere substitution with glutathione, l-cysteine, and l-ascorbate, whereas [Cu(PPP4pT)Cl] demonstrated partial substitution. The role of glutathione in all three latter reactions is significant, given the greater reactivity of the selenosemicarbazone, and glutathione's key role in selenosemicarbazone and thiosemicarbazone anticancer activity.
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Affiliation(s)
- Mahendiran Dharmasivam
- Centre for Cancer Cell Biology and Drug Discovery, Institute for Biomedicine and Glycomics, Griffith University, Southport 4215 Queensland, Australia
| | - Stanley Zhang
- Centre for Cancer Cell Biology and Drug Discovery, Institute for Biomedicine and Glycomics, Griffith University, Southport 4215 Queensland, Australia
| | - Xiao Zhao
- Centre for Cancer Cell Biology and Drug Discovery, Institute for Biomedicine and Glycomics, Griffith University, Southport 4215 Queensland, Australia
| | - Vera Richardson
- Centre for Cancer Cell Biology and Drug Discovery, Institute for Biomedicine and Glycomics, Griffith University, Southport 4215 Queensland, Australia
| | - Tharushi P Wijesinghe
- Centre for Cancer Cell Biology and Drug Discovery, Institute for Biomedicine and Glycomics, Griffith University, Southport 4215 Queensland, Australia
| | - Mediha Suleymanoglu
- Centre for Cancer Cell Biology and Drug Discovery, Institute for Biomedicine and Glycomics, Griffith University, Southport 4215 Queensland, Australia
- Department of Medical Biology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34093, Turkey
| | - Mahan Gholam Azad
- Centre for Cancer Cell Biology and Drug Discovery, Institute for Biomedicine and Glycomics, Griffith University, Southport 4215 Queensland, Australia
| | - Paul V Bernhardt
- School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane 4072, Australia
| | - Busra Kaya
- Centre for Cancer Cell Biology and Drug Discovery, Institute for Biomedicine and Glycomics, Griffith University, Southport 4215 Queensland, Australia
| | - Des R Richardson
- Centre for Cancer Cell Biology and Drug Discovery, Institute for Biomedicine and Glycomics, Griffith University, Southport 4215 Queensland, Australia
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
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Kontoghiorghes GJ. New Insights into Aspirin's Anticancer Activity: The Predominant Role of Its Iron-Chelating Antioxidant Metabolites. Antioxidants (Basel) 2024; 14:29. [PMID: 39857363 PMCID: PMC11763074 DOI: 10.3390/antiox14010029] [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: 11/12/2024] [Revised: 12/06/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025] Open
Abstract
Epidemiological studies have suggested that following long-term, low-dose daily aspirin (LTLDA) administration for more than 5 years at 75-100 mg/day, 20-30% of patients (50-80 years old) had a lower risk of developing colorectal cancer (CRC) and about the same proportion in developing iron deficiency anemia (IDA). In cases of IDA, an increase in iron excretion is suspected, which is caused by aspirin chelating metabolites (ACMs): salicylic acid, salicyluric acid, 2,5-dihydroxybenzoic acid, and 2,3-dihydroxybenzoic acid. The ACMs constitute 70% of the administered aspirin dose and have much longer half-lives than aspirin in blood and tissues. The mechanisms of cancer risk reduction in LTLDA users is likely due to the ACM's targeting of iron involved in free radical damage, iron-containing toxins, iron proteins, and associated metabolic pathways such as ferroptosis. The ACMs from non-absorbed aspirin (about 30%) may also mitigate the toxicity of heme and nitroso-heme and other iron toxins from food, which are responsible for the cause of colorectal cancer. The mode of action of aspirin as a chelating antioxidant pro-drug of the ACMs, with continuous presence in LTLDA users, increases the prospect for prophylaxis in cancer and other diseases. It is suggested that the anticancer effects of aspirin depend primarily on the iron-chelating antioxidant activity of the ACMs. The role of aspirin in cancer and other diseases is incomplete without considering its rapid biotransformation and the longer half-life of the ACMs.
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Affiliation(s)
- George J Kontoghiorghes
- Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol 3021, Cyprus
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3
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Rodríguez I, Acosta C, Nieves-Escobar C, Strangmark E, Claudio-Ares O, Vargas Figueroa AI, Soto-Millán AM, M. Orta-Rivera A, Astashkin AV, Tinoco AD. DefNEtTrp: An Iron Dual Chelator Approach for Anticancer Application. JACS AU 2024; 4:4799-4808. [PMID: 39735911 PMCID: PMC11672142 DOI: 10.1021/jacsau.4c00774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 11/22/2024] [Accepted: 11/25/2024] [Indexed: 12/31/2024]
Abstract
Targeting iron metabolism has emerged as a novel therapeutic strategy for the treatment of cancer. As such, iron chelator drugs are repurposed or specifically designed as anticancer agents. Two important chelators, deferasirox (Def) and triapine (Trp), attack the intracellular supply of iron (Fe) and inhibit Fe-dependent pathways responsible for cellular proliferation and metastasis. Trp, in particular, forms a redox active ferrous complex that inactivates the Fe-dependent ribonucleotide reductase (RNR), responsible for DNA replication. Building on recent efforts to employ intracellular Fe chelation for anticancer therapy, this work aimed to develop the Fe dual chelator ligand DefNEtTrp, consisting of the Def and Trp moieties, to exploit their high affinity Fe(II/III) binding and redox modulation. Using UV-vis spectroscopy, EPR spectroscopy, ESI and MALDI-TOF mass spectrometry, and cyclic voltammetry analyses, DefNEtTrp is shown to retain its Fe binding at both chelator moieties and generate a redox active Fe(III) complex Fe3(DefNEtTrp)2 featuring a reduction potential (E 1/2 = +0.103 V vs normal hydrogen electrode) within the biological window. Screened against different cancer cell line types, DefNEtTrp exhibits potent and broad-spectrum antiproliferative and cell death behavior. Its cytotoxicity (IC50 0.77 ± 0.06 μM) is superior to that of unconjugated Def and Trp ligands (IC50 2.6 ± 0.15 μM and 1.1 ± 0.04 μM, respectively) in single-compound and combination treatments and is selective toward cancer cells. The cell death mechanism of the dual chelator is assessed in the context of intracellular labile Fe binding and was found to induce both apoptosis and ferroptosis.
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Affiliation(s)
- Israel Rodríguez
- Department
of Chemistry, University of Puerto Rico,
Río Piedras Campus, Río
Piedras, Puerto Rico 00931, United States
| | - Carmen Acosta
- Department
of Chemistry, University of Puerto Rico,
Río Piedras Campus, Río
Piedras, Puerto Rico 00931, United States
| | - Christopher Nieves-Escobar
- Department
of Chemistry, University of Puerto Rico,
Río Piedras Campus, Río
Piedras, Puerto Rico 00931, United States
| | - Estelle Strangmark
- Department
of Chemistry, University of Puerto Rico,
Río Piedras Campus, Río
Piedras, Puerto Rico 00931, United States
| | - Oscar Claudio-Ares
- Department
of Chemistry, University of Puerto Rico,
Río Piedras Campus, Río
Piedras, Puerto Rico 00931, United States
| | - Adriana I. Vargas Figueroa
- Department
of Chemistry, University of Puerto Rico,
Río Piedras Campus, Río
Piedras, Puerto Rico 00931, United States
| | - Alexandra M. Soto-Millán
- Department
of Chemistry, University of Puerto Rico,
Río Piedras Campus, Río
Piedras, Puerto Rico 00931, United States
| | - Aixa M. Orta-Rivera
- Department
of Chemistry, University of Puerto Rico,
Río Piedras Campus, Río
Piedras, Puerto Rico 00931, United States
| | - Andrei V. Astashkin
- Department
of Chemistry and Biochemistry, The University
of Arizona, Tucson, Arizona 85721-0041, United States
| | - Arthur D. Tinoco
- Department
of Chemistry, University of Puerto Rico,
Río Piedras Campus, Río
Piedras, Puerto Rico 00931, United States
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Brogyanyi T, Kejík Z, Veselá K, Dytrych P, Hoskovec D, Masařik M, Babula P, Kaplánek R, Přibyl T, Zelenka J, Ruml T, Vokurka M, Martásek P, Jakubek M. Iron chelators as mitophagy agents: Potential and limitations. Biomed Pharmacother 2024; 179:117407. [PMID: 39265234 DOI: 10.1016/j.biopha.2024.117407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 08/26/2024] [Accepted: 09/02/2024] [Indexed: 09/14/2024] Open
Abstract
Mitochondrial autophagy (mitophagy) is very important process for the maintenance of cellular homeostasis, functionality and survival. Its dysregulation is associated with high risk and progression numerous serious diseases (e.g., oncological, neurodegenerative and cardiovascular ones). Therefore, targeting mitophagy mechanisms is very hot topic in the biological and medicinal research. The interrelationships between the regulation of mitophagy and iron homeostasis are now becoming apparent. In short, mitochondria are central point for the regulation of iron homeostasis, but change in intracellular cheatable iron level can induce/repress mitophagy. In this review, relationships between iron homeostasis and mitophagy are thoroughly discussed and described. Also, therapeutic applicability of mitophagy chelators in the context of individual diseases is comprehensively and critically evaluated.
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Affiliation(s)
- Tereza Brogyanyi
- BIOCEV, First Faculty of Medicine, Charles University, Vestec 252 50, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague 120 00, Czech Republic; Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, U Nemocnice 5, 1, Prague 28 53, Czech Republic
| | - Zdeněk Kejík
- BIOCEV, First Faculty of Medicine, Charles University, Vestec 252 50, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague 120 00, Czech Republic
| | - Kateřina Veselá
- BIOCEV, First Faculty of Medicine, Charles University, Vestec 252 50, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague 120 00, Czech Republic
| | - Petr Dytrych
- 1st Department of Surgery-Department of Abdominal, Thoracic Surgery and Traumatology, First Faculty of Medicine, Charles University and General University Hospital, U Nemocnice 2, Prague 121 08, Czech Republic
| | - David Hoskovec
- 1st Department of Surgery-Department of Abdominal, Thoracic Surgery and Traumatology, First Faculty of Medicine, Charles University and General University Hospital, U Nemocnice 2, Prague 121 08, Czech Republic
| | - Michal Masařik
- BIOCEV, First Faculty of Medicine, Charles University, Vestec 252 50, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague 120 00, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno CZ-625 00, Czech Republic; Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno 625 00, Czech Republic
| | - Petr Babula
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno CZ-625 00, Czech Republic
| | - Robert Kaplánek
- BIOCEV, First Faculty of Medicine, Charles University, Vestec 252 50, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague 120 00, Czech Republic
| | - Tomáš Přibyl
- Department of Biochemistry and Microbiology, University of Chemistry and Technology, Prague, Prague 166 28, Czech Republic
| | - Jaroslav Zelenka
- Department of Biochemistry and Microbiology, University of Chemistry and Technology, Prague, Prague 166 28, Czech Republic
| | - Tomáš Ruml
- Department of Biochemistry and Microbiology, University of Chemistry and Technology, Prague, Prague 166 28, Czech Republic
| | - Martin Vokurka
- Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, U Nemocnice 5, 1, Prague 28 53, Czech Republic
| | - Pavel Martásek
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague 120 00, Czech Republic
| | - Milan Jakubek
- BIOCEV, First Faculty of Medicine, Charles University, Vestec 252 50, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague 120 00, Czech Republic.
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5
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Mo M, Pan L, Deng L, Liang M, Xia N, Liang Y. Iron Overload Induces Hepatic Ferroptosis and Insulin Resistance by Inhibiting the Jak2/stat3/slc7a11 Signaling Pathway. Cell Biochem Biophys 2024; 82:2079-2094. [PMID: 38801513 DOI: 10.1007/s12013-024-01315-8] [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] [Accepted: 05/13/2024] [Indexed: 05/29/2024]
Abstract
Recent studies showed that patients with iron overload had increased risk of insulin resistance or diabetes. Ferroptosis is a new type of cell death mainly caused by iron-dependent oxidative damage. In the present study, we investigated potential mechanisms of iron overload induced hepatic ferroptosis and insulin resistance through in vivo and in vitro experiments. In vivo, the mice models of iron overload were established by intraperitoneal injection of iron dextran. The changes of body weight, serum ferritin and blood glucose were measured. Hematoxylin-eosin (HE) and Perl's stainings were used to observe the pathological changes and iron deposition in the liver of mice. In vitro, HepG2 cells were treated with ferric ammonium citrate (FAC, 9 mmol/L, 24 h) to establish the cell models of iron overload. The labile iron pool, cell viability, glucose consumption and glycogen contents were measured. The ultrastructure of mitochondria was observed by transmission electron microscope (TEM). The malondialdehyde (MDA) and glutathione (GSH) kits were used to detect lipid peroxidation in liver tissues of mice and HepG2 cells. RT-PCR and Western blot were used to detect the mRNA and protein expression levels of ferroptosis factors and JAK2/STAT3 signaling pathway. In this study, we used the iron chelator deferasirox in mice and HepG2 cells. Iron overload caused weight loss, elevated serum ferritin, fasting blood glucose, fasting insulin, HOMA-IR, impaired glucose tolerance, and decreased insulin sensitivity in mice. HE staining and Perls staining showed clumps of iron deposition in the liver of iron overload mice. Iron overload could reduce the glucose consumption, increase MDA contents of HepG2 cells, while reduce glycogen and GSH contents in liver tissues of mice and HepG2 cells. TEM showed deletion of mitochondrial ridge and rupture of outer membrane in HepG2 cells with iron overload. Iron chelator deferasirox could significantly improve the above indicators, which might be related to the activation of JAK2/STAT3/SLC7A11 signaling pathway and hepatic ferroptosis. Iron overload could induce hepatic ferroptosis and insulin resistance by inhibiting the JAK2/STAT3/SLC7A11 signaling pathway, and the iron chelator deferasirox might improve hepatic insulin resistance induced by iron overload.
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Affiliation(s)
- Manqiu Mo
- Geriatric Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Ling Pan
- Department of Nephrology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Ling Deng
- Department of Endocrinology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Min Liang
- Geriatric Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Ning Xia
- Geriatric Department of Endocrinology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
| | - Yuzhen Liang
- Department of Endocrinology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China.
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6
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Sung YS, Tomat E. Quinoline-based tetrazolium prochelators: formazan release, iron sequestration, and antiproliferative efficacy in cancer cells. Chem Commun (Camb) 2024; 60:6150-6153. [PMID: 38804255 PMCID: PMC11568512 DOI: 10.1039/d4cc01523a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Iron-binding strategies in anticancer drug design target the key role of iron in cancer growth. The incorporation of a quinoline moiety in the design of tetrazolium-based prochelators facilitates their intracellular reduction/activation to iron-binding formazans. The new prochelators are antiproliferative at submicromolar levels, induce apoptosis and cell cycle arrest, and impact iron signaling in cancer cells.
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Affiliation(s)
- Yu-Shien Sung
- Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721-0041, USA.
| | - Elisa Tomat
- Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721-0041, USA.
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7
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Bhat AA, Moglad E, Bansal P, Kaur H, Deorari M, Thapa R, Almalki WH, Kazmi I, Alzarea SI, Kukreti N, Ali H. Pollutants to pathogens: The role of heavy metals in modulating TGF-β signaling and lung cancer risk. Pathol Res Pract 2024; 256:155260. [PMID: 38493726 DOI: 10.1016/j.prp.2024.155260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/05/2024] [Accepted: 03/08/2024] [Indexed: 03/19/2024]
Abstract
Lung cancer is a malignant tumor that develops in the lungs due to the uncontrolled growth of aberrant cells. Heavy metals, such as arsenic, cadmium, mercury, and lead, are metallic elements characterized by their high atomic weights and densities. Anthropogenic activities, such as industrial operations and pollution, have the potential to discharge heavy metals into the environment, hence presenting hazards to ecosystems and human well-being. The TGF-β signalling pathways have a crucial function in controlling several cellular processes, with the ability to both prevent and promote tumor growth. TGF-β regulates cellular responses by interacting in both canonical and non-canonical signalling pathways. Research employing both in vitro and in vivo models has shown that heavy metals may trigger TGF-β signalling via complex molecular pathways. Experiments conducted in a controlled laboratory environment show that heavy metals like cadmium and arsenic may directly bind to TGF-β receptors, leading to alterations in their structure that enable the receptor to be phosphorylated. Activation of this route sets in motion subsequent signalling cascades, most notably the canonical Smad pathway. The development of lung cancer has been linked to heavy metals, which are ubiquitous environmental pollutants. To grasp the underlying processes, it is necessary to comprehend their molecular effect on TGF-β pathways. With a particular emphasis on its consequences for lung cancer, this abstract delves into the complex connection between exposure to heavy metals and the stimulation of TGF-β signalling.
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Affiliation(s)
- Asif Ahmad Bhat
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Mahal Road, Jaipur 302017, India
| | - Ehssan Moglad
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al Kharj 11942, Saudi Arabia
| | - Pooja Bansal
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, Karnataka 560069, India; Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Harpreet Kaur
- School of Basic & Applied Sciences, Shobhit University, Gangoh, Uttar Pradesh 247341, India; Department of Health & Allied Sciences, Arka Jain University, Jamshedpur, Jharkhand 831001, India
| | - Mahamedha Deorari
- Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India
| | - Riya Thapa
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura, Mahal Road, Jaipur 302017, India
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia
| | - Neelima Kukreti
- School of Pharmacy, Graphic Era Hill University, Dehradun 248007, India
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India; Department of Pharmacology, Kyrgyz State Medical College, Bishkek, Kyrgyzstan.
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8
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Abdel-Wahab ND, Kabil MF, El-Sherbiny IM, Salama MF, El-Sayed G, El-Sherbini ES. Potential anticancer effect of free and nanoformulated Deferasirox for breast cancer treatment: in-vitro and in-vivo evaluation. Drug Dev Ind Pharm 2024; 50:223-235. [PMID: 38305197 DOI: 10.1080/03639045.2024.2314189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 01/30/2024] [Indexed: 02/03/2024]
Abstract
BACKGROUND Breast cancer (BC) stands as the second-leading cause of mortality among women worldwide. Many chemotherapeutic treatments for BC come with significant adverse effects. Additionally, BC is recognized as one of the most resistant forms of malignancy to treatment. Consequently, there exists a critical need for innovative therapeutic agents that are both highly effective and exhibit reduced toxicity and side effects for patients. Deferasirox (DFX), an iron-chelating drug approved by the FDA for oral use, emerges as a promising contender in the fight against BC proliferation. DFX, primarily administered orally, is utilized to address chronic iron excess resulting from blood transfusions, and it is the inaugural treatment for chronic iron overload syndrome. However, DFX encounters limitations due to its poor water solubility. AIM This study aimed at incorporating DFX into lipid nanocapsules (DFX-LNCs) followed by investigating the anticancer effect of the DFX nanoform as compared to free DFX in-vitro and on an orthotopic BC mouse model in-vivo. METHODS The DFX-LNCs was prepared and imaged using TEM and also characterized in terms of particle size (PS), zeta potential (ZP), and polydispersity index (PDI) using DLS. Moreover, drug release, cytotoxicity, and anticancer effect were assessed in-vitro, and in-vivo. RESULTS The results revealed that DFX-LNCs are more cytotoxic than free DFX with IC50 of 4.417 µg/ml and 16.114 µg/ml, respectively, while the plain LNCs didn't show any cytotoxic effect on the 4T1 cell line (IC50 = 122.797 µg/ml). Besides, the apoptotic effect of DFX-LNCs was more pronounced than that of free DFX, as evidenced by Annexin V/PI staining, increased BAX expression, and decreased expression of BcL-2. Moreover, DFX-LNCs showed a superior antitumor effect in-vivo with potent antioxidant and anti-proliferative effects. CONCLUSION The newly developed DFX nanoform demonstrated a high potential as a promising therapeutic agent for BC treatment.
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Affiliation(s)
- Nadeen Diaa Abdel-Wahab
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Mansoura University, Egypt
| | - Mohamed Fawzi Kabil
- Nanomedicine Research Labs, Center for Materials Science, Zewail City of Science and Technology, Giza, Egypt
| | - Ibrahim M El-Sherbiny
- Nanomedicine Research Labs, Center for Materials Science, Zewail City of Science and Technology, Giza, Egypt
| | - Mohamed F Salama
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Mansoura University, Egypt
| | - Gehad El-Sayed
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Mansoura University, Egypt
| | - El-Said El-Sherbini
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Mansoura University, Egypt
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9
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Kozarski M, Klaus A, Špirović-Trifunović B, Miletić S, Lazić V, Žižak Ž, Vunduk J. Bioprospecting of Selected Species of Polypore Fungi from the Western Balkans. Molecules 2024; 29:314. [PMID: 38257227 PMCID: PMC10819588 DOI: 10.3390/molecules29020314] [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: 11/24/2023] [Revised: 12/27/2023] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
Growing mushrooms means meeting challenges while aiming for sustainability and circularity. Wherever the producer is located, commercial strains are the same originating from several producers. Customized strains adapted to local conditions are urgently needed. Before introducing new species to the strain development pipeline, the chemical characterization and biological activity of wild ones need to be assessed. Accordingly, the mycoceutical potential of five polypore mushroom species from Serbia was evaluated including: secondary metabolite composition, oxidative damage prevention, anti-tyrosinase, and anti-angiotensin converting enzyme (ACE). The phenolic pattern was comparable in all samples, but the amounts of specific chemicals varied. Hydroxybenzoic acids were the primary components. All samples had varying quantities of ascorbic acid, carotene, and lycopene, and showed a pronounced inhibition of lipid peroxidation (LPx) and ability to scavenge HO•. Extracts were more potent tyrosinase inhibitors but unsuccessful when faced with ACE. Fomitopsis pinicola had the strongest anti-tumor efficacy while Ganoderma lucidum demonstrated strong selectivity in anti-tumor effect in comparison to normal cells. The evaluated species provided a solid foundation for commercial development while keeping local ecology in mind.
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Affiliation(s)
- Maja Kozarski
- Institute for Food Technology and Biochemistry, Faculty of Agriculture, University of Belgrade, Nemanjina 6, 11080 Belgrade, Serbia; (M.K.); (A.K.); (V.L.)
| | - Anita Klaus
- Institute for Food Technology and Biochemistry, Faculty of Agriculture, University of Belgrade, Nemanjina 6, 11080 Belgrade, Serbia; (M.K.); (A.K.); (V.L.)
| | - Bojana Špirović-Trifunović
- Institute for Phytomedicine, Faculty of Agriculture, University of Belgrade, Nemanjina 6, 11080 Belgrade, Serbia;
| | - Srdjan Miletić
- Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Njegoševa 12, 11000 Belgrade, Serbia;
| | - Vesna Lazić
- Institute for Food Technology and Biochemistry, Faculty of Agriculture, University of Belgrade, Nemanjina 6, 11080 Belgrade, Serbia; (M.K.); (A.K.); (V.L.)
| | - Željko Žižak
- Institute of Oncology and Radiology of Serbia, Paterova 14, 11000 Belgrade, Serbia;
| | - Jovana Vunduk
- Institute of General and Physical Chemistry, Studentski trg 12/V, 11158 Belgrade, Serbia
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10
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Yasan GT, Gunel-Ozcan A. Hypoxia and Hypoxia Mimetic Agents As Potential Priming Approaches to Empower Mesenchymal Stem Cells. Curr Stem Cell Res Ther 2024; 19:33-54. [PMID: 36642875 DOI: 10.2174/1574888x18666230113143234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/12/2022] [Accepted: 11/04/2022] [Indexed: 01/17/2023]
Abstract
Mesenchymal stem cells (MSC) exhibit self-renewal capacity and multilineage differentiation potential, making them attractive for research and clinical application. The properties of MSC can vary depending on specific micro-environmental factors. MSC resides in specific niches with low oxygen concentrations, where oxygen functions as a metabolic substrate and a signaling molecule. Conventional physical incubators or chemically hypoxia mimetic agents are applied in cultures to mimic the original low oxygen tension settings where MSC originated. This review aims to focus on the current knowledge of the effects of various physical hypoxic conditions and widely used hypoxia-mimetic agents-PHD inhibitors on mesenchymal stem cells at a cellular and molecular level, including proliferation, stemness, differentiation, viability, apoptosis, senescence, migration, immunomodulation behaviors, as well as epigenetic changes.
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Affiliation(s)
| | - Aysen Gunel-Ozcan
- Department of Stem Cell Sciences, Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey
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11
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Huang S, Zhang D, Yi X, Liu C, Jian C, Yu A. 3-AP inhibits the growth of human osteosarcoma by decreasing the activity of the iron-dependent pathway. Med Oncol 2023; 40:353. [PMID: 37952032 DOI: 10.1007/s12032-023-02215-2] [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: 09/11/2023] [Accepted: 10/08/2023] [Indexed: 11/14/2023]
Abstract
3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) has broad-spectrum antitumor activity. However, its role in osteosarcoma (OS) remains unclear. Therefore, this study explored the effects of 3-AP on OS in vitro and in vivo using three human OS cell lines (MG-63, U2-OS, and 143B) and a nude mice model generated by transplanting 143B cells. The cells and mice were treated with DMSO (control) or gradient concentrations of 3-AP. Then, various assays (e.g., cell counting kit-8, flow cytometry, immunohistochemistry, and western blotting) were performed to assess cell viability and apoptosis levels, as well as γH2A.X (DNA damage correlation), ribonucleotide reductase catalytic subunit M1 and M2 (RRM1 and RRM2, respectively) protein levels (iron-dependent correlation). 3-AP time- and dose-dependably suppressed growth and induced apoptosis in all three OS cell lines, and ferric ammonium citrate (FAC) blocked these effects. Moreover, 3-AP decreased RRM2 and total ribonucleotide reductase (RRM1 plus RRM2) protein expression but significantly increased γH2A.X expression; treatment did not affect RRM1 expression. Again, FAC treatment attenuated these effects. In vivo, the number of apoptotic cells in the tumor slices increased in the 3-AP-treated mice compared to the control mice. 3-AP treatment also decreased Ki-67 and p21 expression, suggesting inhibited OS growth. Furthermore, the expression of RRM1, RRM2, and transferrin receptor protein 1 (i.e., Tfr1) indicated that 3-AP inhibited OS growth via an iron-dependent pathway. In conclusion, 3-AP exhibits anticancer activity in OS by decreasing the activity of iron-dependent pathways, which could be a promising therapeutic strategy for OS.
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Affiliation(s)
- Siyuan Huang
- Department of Orthopedics, Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuhan, 430071, Hubei, People's Republic of China
| | - Dong Zhang
- Department of Orthopedics, Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuhan, 430071, Hubei, People's Republic of China
| | - Xinzeyu Yi
- Department of Orthopedics, Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuhan, 430071, Hubei, People's Republic of China
| | - Changjiang Liu
- Department of Orthopedics, Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuhan, 430071, Hubei, People's Republic of China
| | - Chao Jian
- Department of Orthopedics, Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuhan, 430071, Hubei, People's Republic of China.
- Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, People's Republic of China.
| | - Aixi Yu
- Department of Orthopedics, Trauma and Microsurgery, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuhan, 430071, Hubei, People's Republic of China.
- Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei, People's Republic of China.
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Fujisawa K, Matsumoto T, Yamamoto N, Yamasaki T, Takami T. Metabolic Analysis of DFO-Resistant Huh7 Cells and Identification of Targets for Combination Therapy. Metabolites 2023; 13:1073. [PMID: 37887398 PMCID: PMC10609263 DOI: 10.3390/metabo13101073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/06/2023] [Accepted: 10/10/2023] [Indexed: 10/28/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most refractory cancers with a high rate of recurrence. Iron is an essential trace element, and iron chelation has garnered attention as a novel therapeutic strategy for cancer. Since intracellular metabolism is significantly altered by inhibiting various proteins by iron chelation, we investigated combination anticancer therapy targeting metabolic changes that are forcibly modified by iron chelator administration. The deferoxamine (DFO)-resistant cell lines were established by gradually increasing the DFO concentration. Metabolomic analysis was conducted to evaluate the metabolic alterations induced by DFO administration, aiming to elucidate the resistance mechanism in DFO-resistant strains and identify potential novel therapeutic targets. Metabolom analysis of the DFO-resistant Huh7 cells revealed enhanced glycolysis and salvage cycle, alternations in glutamine metabolism, and accumulation of dipeptides. Huh7 cultured in the absence of glutamine showed enhanced sensitivity to DFO, and glutaminase inhibitor (CB839) showed a synergistic effect with DFO. Furthermore, the effect of DFO was enhanced by an autophagy inhibitor (chloroquine) in vitro. DFO-induced metabolic changes are specific targets for the development of efficient anticancer combinatorial therapies using DFO. These findings will be useful for the development of new cancer therapeutics in refractory liver cancer.
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Affiliation(s)
- Koichi Fujisawa
- Department of Environmental Oncology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yamaguchi University, Minami Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan; (T.M.); (N.Y.); (T.T.)
| | - Toshihiko Matsumoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yamaguchi University, Minami Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan; (T.M.); (N.Y.); (T.T.)
| | - Naoki Yamamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yamaguchi University, Minami Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan; (T.M.); (N.Y.); (T.T.)
- Amaguchi University Health Administration Center, 1677-1 Yoshida, Yamaguchi 753-8511, Japan
| | - Takahiro Yamasaki
- Department of Oncology and Laboratory Medicine, Graduate School of Medicine, Yamaguchi University, Minami Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan;
| | - Taro Takami
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Yamaguchi University, Minami Kogushi 1-1-1, Ube, Yamaguchi 755-8505, Japan; (T.M.); (N.Y.); (T.T.)
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13
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Althobaiti F, Sahyon HA, Shanab MMAH, Aldhahrani A, Helal MA, Khireldin A, Shoair AGF, Almalki ASA, Fathy AM. A comparative study of novel ruthenium(III) and iron(III) complexes containing uracil; docking and biological studies. J Inorg Biochem 2023; 247:112308. [PMID: 37441923 DOI: 10.1016/j.jinorgbio.2023.112308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 06/25/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023]
Abstract
Structural and biological studies were conducted on the novel complexes [Fe(U)2(H2O)2]Cl3 (FeU) and [Ru(U)2(H2O)2]Cl3 (RuU) (U = 5,6-Diamino-1,3-dimethylpyrimidine-2,4(1H,3H)-dione) to develop an anticancer drug candidate. The two complexes have been synthesized and characterized. Based on our findings, these complexes have octahedral geometry. The DNA-binding study proved that both complexes coordinated with CT-DNA. The docking study confirmed the potency of both complexes in downregulating the topoisomerase I protein through their high binding affinity. Biological studies have established that both complexes can act as potent anticancer agents against three cancer cell lines. RuU or FeU complexes induce apoptosis in breast cancer cells by increasing caspase9 protein and inhibiting proliferating cell nuclear antigen (PCNA) activity. In addition, both complexes down-regulate topoisomerase I expression in breast cancer cells. Therefore, the RuU and FeU complexes' anticancer activities were mediated via both apoptosis induction and topoisomerase I down-regulation. In conclusion, both complexes have dual anticancer activity pathways that may be responsible for the selective cytotoxicity of the complexes. This makes them more suitable for the development of novel cancer treatment strategies.
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Affiliation(s)
- Fayez Althobaiti
- Department of Biotechnology, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
| | - Heba A Sahyon
- Chemistry Department, Faculty of Science, Kafrelsheikh University, 33516 Kafrelsheikh, Egypt.
| | - Mai M A H Shanab
- Department of Chemistry, College of Sciences and Humanities Studies (Girls section), Hawtat Bani Tamim 11149, Prince Sattam Bin Abdulaziz University, P.O. Box:13, Saudi Arabia.
| | - Adil Aldhahrani
- Clinical Laboratory Science Department, Turabah University College, Taif University, Taif 21995, Saudi Arabia.
| | - Marihan A Helal
- Chemistry Department, Faculty of Science, Damietta University, Damietta, Egypt
| | - Awad Khireldin
- Air transport management, Singapore Institute of Technology (SIT), Singapore.
| | - Abdel Ghany F Shoair
- Department of Science and Technology, University College-Ranyah, postcode 21975, Taif University, Saudi Arabia; High Altitude Research Center, Taif University, 21944, Saudi Arabia.
| | | | - Ahmed M Fathy
- Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt
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Callejón-Leblic B, Sánchez Espirilla S, Gotera-Rivera C, Santana R, Díaz-Olivares I, Marín JM, Macario CC, Cosio BG, Fuster A, García IS, de-Torres JP, Feu Collado N, Cabrera Lopez C, Amado Diago C, Romero Plaza A, Fraysse LAP, Márquez Martín E, Marín Royo M, Balcells Vilarnau E, Llunell Casanovas A, Martínez González C, Galdíz Iturri JB, Lacárcel Bautista C, Gómez-Ariza JL, Pereira-Vega A, Seijo L, López-Campos JL, Peces-Barba G, García-Barrera T. Metallomic Signatures of Lung Cancer and Chronic Obstructive Pulmonary Disease. Int J Mol Sci 2023; 24:14250. [PMID: 37762552 PMCID: PMC10532173 DOI: 10.3390/ijms241814250] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/07/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Lung cancer (LC) is the leading cause of cancer deaths, and chronic obstructive pulmonary disease (COPD) can increase LC risk. Metallomics may provide insights into both of these tobacco-related diseases and their shared etiology. We conducted an observational study of 191 human serum samples, including those of healthy controls, LC patients, COPD patients, and patients with both COPD and LC. We found 18 elements (V, Al, As, Mn, Co, Cu, Zn, Cd, Se, W, Mo, Sb, Pb, Tl, Cr, Mg, Ni, and U) in these samples. In addition, we evaluated the elemental profiles of COPD cases of varying severity. The ratios and associations between the elements were also studied as possible signatures of the diseases. COPD severity and LC have a significant impact on the elemental composition of human serum. The severity of COPD was found to reduce the serum concentrations of As, Cd, and Tl and increased the serum concentrations of Mn and Sb compared with healthy control samples, while LC was found to increase Al, As, Mn, and Pb concentrations. This study provides new insights into the effects of LC and COPD on the human serum elemental profile that will pave the way for the potential use of elements as biomarkers for diagnosis and prognosis. It also sheds light on the potential link between the two diseases, i.e., the evolution of COPD to LC.
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Affiliation(s)
- Belén Callejón-Leblic
- Department of Chemistry, Research Center for Natural Resources, Health and the Environment (RENSMA), Faculty of Experimental Sciences, University of Huelva, Campus El Carmen, Fuerzas Armadas Ave., 21007 Huelva, Spain; (B.C.-L.); (S.S.E.); (J.L.G.-A.)
| | - Saida Sánchez Espirilla
- Department of Chemistry, Research Center for Natural Resources, Health and the Environment (RENSMA), Faculty of Experimental Sciences, University of Huelva, Campus El Carmen, Fuerzas Armadas Ave., 21007 Huelva, Spain; (B.C.-L.); (S.S.E.); (J.L.G.-A.)
- Department of Chemistry, Faculty of Sciences, National University of San Antonio Abad of Cusco, Av. de La Cultura, Cusco 773, Peru
| | - Carolina Gotera-Rivera
- IIS-Jiménez Díaz Foundation, ISCIII-CIBERES, Reyes Católicos Ave., 28040 Madrid, Spain; (C.G.-R.); (R.S.)
| | - Rafael Santana
- IIS-Jiménez Díaz Foundation, ISCIII-CIBERES, Reyes Católicos Ave., 28040 Madrid, Spain; (C.G.-R.); (R.S.)
| | - Isabel Díaz-Olivares
- Beturia Andalusian Foundation for Health Research (FABIS), Ronda Norte, s/n, 21005 Huelva, Spain;
| | - José M. Marín
- Miguel Servet Hospital-IIS Aragon, ISCIII-CIBERES, Paseo de Isabel la Católica, 1-3, 50009 Zaragoza, Spain;
| | - Ciro Casanova Macario
- Pulmonary Department—Research Unit, Hospital Universitario Nuestra Señora de Candelaria, CIBERES, ISCIII, Universidad de La Laguna, Padre Herrera, s/n, 38200 Santa Cruz de Tenerife, Spain;
| | - Borja García Cosio
- Son Espases Hospital, IdISBa, ISCIII-CIBERES, Valldemossa Road, 79, 07120 Palma De Mallorca, Spain;
| | - Antonia Fuster
- Son Llàtzer Hospital, C. de Manacor, 07198 Palma, Spain;
| | - Ingrid Solanes García
- Santa Creu i Sant Pau Hospital, Carrer de St. Antoni Maria Claret, 167, 08025 Barcelona, Spain;
| | - Juan P. de-Torres
- University Clinic of Navarra, Pío XII Ave., 36, 31008 Pamplona, Spain;
| | - Nuria Feu Collado
- Reina Sofía Hospital, Maimonides Institute for Biomedical Research of Córdoba, Menéndez Pidal Ave., s/n, 14004 Córdoba, Spain;
| | - Carlos Cabrera Lopez
- University Hospital of Gran Canaria Dr. Negrín, Respiratory Service, C. Pl. Barranco de la Ballena, s/n, 35010 Las Palmas de Gran Canarias, Spain;
| | | | | | | | - Eduardo Márquez Martín
- Virgen del Rocío Hospital, Institute of Biomedicine of Seville (IBiS), ISCIII-CIBERES, Manuel Siurot Ave., s/n, 41013 Seville, Spain;
| | | | - Eva Balcells Vilarnau
- Hospital del Mar, ISCIII-CIBERES, Paseo Marítimo de la Barceloneta, 25, 29, 08003 Barcelona, Spain;
| | | | | | | | | | - José Luis Gómez-Ariza
- Department of Chemistry, Research Center for Natural Resources, Health and the Environment (RENSMA), Faculty of Experimental Sciences, University of Huelva, Campus El Carmen, Fuerzas Armadas Ave., 21007 Huelva, Spain; (B.C.-L.); (S.S.E.); (J.L.G.-A.)
| | - Antonio Pereira-Vega
- Pneumology Area of the Juan Ramón Jiménez Hospital, Ronda Norte, s/n, 21005 Huelva, Spain; (L.A.P.F.); (A.P.-V.)
| | - Luis Seijo
- University Clinic of Navarra, ISCIII-CIBERES, Monforte de Lemos Ave., 28029 Madrid, Spain;
| | - José Luis López-Campos
- Medical-Surgical Unit for Respiratory Diseases, Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, University of Seville, Manuel Siurot Ave., s/n, 41013 Sevilla, Spain;
- Center for Biomedical Research in Respiratory Diseases Network (CIBERES), Carlos III Health Institute, Av. de Monforte de Lemos, 3–5, 28029 Madrid, Spain
| | - Germán Peces-Barba
- IIS-Jiménez Díaz Foundation, ISCIII-CIBERES, Reyes Católicos Ave., 28040 Madrid, Spain; (C.G.-R.); (R.S.)
| | - Tamara García-Barrera
- Department of Chemistry, Research Center for Natural Resources, Health and the Environment (RENSMA), Faculty of Experimental Sciences, University of Huelva, Campus El Carmen, Fuerzas Armadas Ave., 21007 Huelva, Spain; (B.C.-L.); (S.S.E.); (J.L.G.-A.)
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15
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Wei H, Li Z, Zhao Y, Zhu S, Wen S, Quan C. Six-transmembrane epithelial antigen of prostate 3 (STEAP3) is a potential prognostic biomarker in clear cell renal cell carcinoma that correlates with M2 macrophage infiltration and epithelial-mesenchymal. Cancer Rep (Hoboken) 2023; 6:e1824. [PMID: 37344930 PMCID: PMC10432435 DOI: 10.1002/cnr2.1824] [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: 01/10/2023] [Revised: 03/30/2023] [Accepted: 04/10/2023] [Indexed: 06/23/2023] Open
Abstract
BACKGROUND The six-transmembrane epithelial antigen of the prostate 3 (STEAP3) is a metalloreductase, which is essential for iron uptake. Existing literature has shown that STEAP3 may perform an important role in the onset and progression of tumors. Nonetheless, a complete pan-cancer investigation of the prognostic significance and immune properties of STEAP3 is currently unavailable. AIMS As part of our investigation into the possible functions of STEAP3 in malignancies, we conducted a comprehensive analysis to examine the prognostic value and immune features of STEAP3 in human pan-cancer. METHODS AND RESULTS R and Cytoscape programs were applied to analyze and visualize the data. The expression of STEAP3 in both cell lines and tissues was measured utilizing a variety of approaches. Using the shRNA knockdown technique, we tested the viability of the A498 and 786-O cell lines and validated their functions. Both CCK-8 and transwell assays were conducted to estimate cell proliferation and invasion. The expression of STEAP3 was substantially elevated and was shown to be linked to prognosis in the majority of malignancies, notably in clear cell renal cell carcinoma (ccRCC). In addition, the expression of STEAP3 was shown to have a strong correlation with immune infiltrates, which in turn triggered the recruitment and polarization of M2 macrophages in ccRCC. The protein STEAP3 shows promise as a predictor of responses to immune-checkpoint blockade (ICB) therapy. Positive links between STEAP3 and the epithelial-mesenchymal transition (EMT), the p53 pathway, and the immune-associated pathways were also found in the enrichment analysis. Our results illustrated that the STEAP3 expression level was substantially elevated in ccRCC tissues and suggested that it could stimulate EMT in ccRCC by downregulating CDH1. CONCLUSION In a diverse range of cancers, STEAP3 might serve as a biomarker for determining the prognosis as well as a predictor of immunotherapy responsiveness. STEAP3 is a novel biological marker for determining prognosis, and it also performs a remarkable function in the promotion of tumor growth in ccRCC by enhancing invasion and EMT, as well as by triggering the recruitment and polarization of M2 macrophages.
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Affiliation(s)
- Haotian Wei
- Department of UrologySecord Affiliated Hospital of Tianjin Medical UniversityTianjinChina
| | - Zhaochen Li
- Department of UrologySecord Affiliated Hospital of Tianjin Medical UniversityTianjinChina
| | - Yang Zhao
- Department of RadiologySecord Affiliated Hospital of Tianjin Medical UniversityTianjinChina
| | - Shimiao Zhu
- Department of UrologySecord Affiliated Hospital of Tianjin Medical UniversityTianjinChina
| | - Simeng Wen
- Department of UrologySecord Affiliated Hospital of Tianjin Medical UniversityTianjinChina
| | - Changyi Quan
- Department of UrologySecord Affiliated Hospital of Tianjin Medical UniversityTianjinChina
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16
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Cardona CJ, Montgomery MR. Iron regulatory proteins: players or pawns in ferroptosis and cancer? Front Mol Biosci 2023; 10:1229710. [PMID: 37457833 PMCID: PMC10340119 DOI: 10.3389/fmolb.2023.1229710] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 06/21/2023] [Indexed: 07/18/2023] Open
Abstract
Cells require iron for essential functions like energy production and signaling. However, iron can also engage in free radical formation and promote cell proliferation thereby contributing to both tumor initiation and growth. Thus, the amount of iron within the body and in individual cells is tightly regulated. At the cellular level, iron homeostasis is maintained post-transcriptionally by iron regulatory proteins (IRPs). Ferroptosis is an iron-dependent form of programmed cell death with vast chemotherapeutic potential, yet while IRP-dependent targets have established roles in ferroptosis, our understanding of the contributions of IRPs themselves is still in its infancy. In this review, we present the growing circumstantial evidence suggesting that IRPs play critical roles in the adaptive response to ferroptosis and ferroptotic cell death and describe how this knowledge can be leveraged to target neoplastic iron dysregulation more effectively.
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Kontoghiorghes GJ. Deferiprone and Iron-Maltol: Forty Years since Their Discovery and Insights into Their Drug Design, Development, Clinical Use and Future Prospects. Int J Mol Sci 2023; 24:ijms24054970. [PMID: 36902402 PMCID: PMC10002863 DOI: 10.3390/ijms24054970] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 02/24/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
The historical insights and background of the discovery, development and clinical use of deferiprone (L1) and the maltol-iron complex, which were discovered over 40 years ago, highlight the difficulties, complexities and efforts in general orphan drug development programs originating from academic centers. Deferiprone is widely used for the removal of excess iron in the treatment of iron overload diseases, but also in many other diseases associated with iron toxicity, as well as the modulation of iron metabolism pathways. The maltol-iron complex is a recently approved drug used for increasing iron intake in the treatment of iron deficiency anemia, a condition affecting one-third to one-quarter of the world's population. Detailed insights into different aspects of drug development associated with L1 and the maltol-iron complex are revealed, including theoretical concepts of invention; drug discovery; new chemical synthesis; in vitro, in vivo and clinical screening; toxicology; pharmacology; and the optimization of dose protocols. The prospects of the application of these two drugs in many other diseases are discussed under the light of competing drugs from other academic and commercial centers and also different regulatory authorities. The underlying scientific and other strategies, as well as the many limitations in the present global scene of pharmaceuticals, are also highlighted, with an emphasis on the priorities for orphan drug and emergency medicine development, including the roles of the academic scientific community, pharmaceutical companies and patient organizations.
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Affiliation(s)
- George J Kontoghiorghes
- Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol 3021, Cyprus
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18
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Tisserand J, Randrian V, Paccalin M, Saulnier PJ, Arviset M, Fourmy A, Arriudarré V, Jamet A, Moreno Y, Valéro S, Liuu E. Association between Iron Deficiency and Survival in Older Patients with Cancer. Cancers (Basel) 2023; 15:cancers15051533. [PMID: 36900329 PMCID: PMC10000607 DOI: 10.3390/cancers15051533] [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: 01/15/2023] [Revised: 02/22/2023] [Accepted: 02/26/2023] [Indexed: 03/04/2023] Open
Abstract
BACKGROUND iron deficiency (ID) is frequent in older patients. PURPOSE to evaluate the association between ID and survival in patients ≥ 75 years old with confirmed solid tumors. METHODS a retrospective monocentric study including patients between 2009 and 2018. ID, absolute ID (AID) and functional ID (FID) were defined according to the European Society for Medical Oncology (ESMO) criteria. Severe ID was defined by a ferritin level < 30 µg/L. RESULTS in total, 556 patients were included, the mean age was 82 (±4.6) years, 56% were male, the most frequent cancer was colon cancer (19%, n = 104), and metastatic cancers were found in 38% (n = 211). Median follow-up time: 484 [190-1377] days. In anemic patients, ID and FID were independently associated with an increased risk of mortality (respectively, HR 1.51; p = 0.0065 and HR 1.73; p = 0.0007). In non-anemic patients, FID was independently associated with better survival (HR 0.65; p = 0.0495). CONCLUSION in our study, ID was significantly associated with survival, and with better survival for patients without anemia. These results suggest that attention should be paid to the iron status in older patients with tumors and raise questions about the prognostic value of iron supplementation for iron-deficient patients without anemia.
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Affiliation(s)
- Julie Tisserand
- Geriatrics Department, Poitiers University Hospital, 86000 Poitiers, France
| | - Violaine Randrian
- ProDiCeT, CHU Poitiers, Université de Poitiers, 86000 Poitiers, France
- Gastroenterology and Hepatology Department, Poitiers University Hospital, 86000 Poitiers, France
| | - Marc Paccalin
- Geriatrics Department, Poitiers University Hospital, 86000 Poitiers, France
- University Hospital Poitiers, University of Poitiers, INSERM CIC 1402, 2 rue de la Milétrie, CEDEX, 86021 Poitiers, France
| | - Pierre-Jean Saulnier
- University Hospital Poitiers, University of Poitiers, INSERM CIC 1402, 2 rue de la Milétrie, CEDEX, 86021 Poitiers, France
| | - Marine Arviset
- Geriatrics Department, Poitiers University Hospital, 86000 Poitiers, France
| | - Arthur Fourmy
- Geriatrics Department, Poitiers University Hospital, 86000 Poitiers, France
| | - Victor Arriudarré
- Geriatrics Department, Poitiers University Hospital, 86000 Poitiers, France
| | - Amélie Jamet
- Geriatrics Department, Poitiers University Hospital, 86000 Poitiers, France
| | - Yvan Moreno
- Geriatrics Department, Poitiers University Hospital, 86000 Poitiers, France
| | - Simon Valéro
- Geriatrics Department, Poitiers University Hospital, 86000 Poitiers, France
| | - Evelyne Liuu
- Geriatrics Department, Poitiers University Hospital, 86000 Poitiers, France
- University Hospital Poitiers, University of Poitiers, INSERM CIC 1402, 2 rue de la Milétrie, CEDEX, 86021 Poitiers, France
- Correspondence:
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El-Tanani M, Nsairat H, Mishra V, Mishra Y, Aljabali AAA, Serrano-Aroca Á, Tambuwala MM. Ran GTPase and Its Importance in Cellular Signaling and Malignant Phenotype. Int J Mol Sci 2023; 24:3065. [PMID: 36834476 PMCID: PMC9968026 DOI: 10.3390/ijms24043065] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 01/10/2023] [Accepted: 01/11/2023] [Indexed: 02/08/2023] Open
Abstract
Ran is a member of the Ras superfamily of proteins, which primarily regulates nucleocytoplasmic trafficking and mediates mitosis by regulating spindle formation and nuclear envelope (NE) reassembly. Therefore, Ran is an integral cell fate determinant. It has been demonstrated that aberrant Ran expression in cancer is a result of upstream dysregulation of the expression of various factors, such as osteopontin (OPN), and aberrant activation of various signaling pathways, including the extracellular-regulated kinase/mitogen-activated protein kinase (ERK/MEK) and phosphatidylinositol 3-kinase/Protein kinase B (PI3K/Akt) pathways. In vitro, Ran overexpression has severe effects on the cell phenotype, altering proliferation, adhesion, colony density, and invasion. Therefore, Ran overexpression has been identified in numerous types of cancer and has been shown to correlate with tumor grade and the degree of metastasis present in various cancers. The increased malignancy and invasiveness have been attributed to multiple mechanisms. Increased dependence on Ran for spindle formation and mitosis is a consequence of the upregulation of these pathways and the ensuing overexpression of Ran, which increases cellular dependence on Ran for survival. This increases the sensitivity of cells to changes in Ran concentration, with ablation being associated with aneuploidy, cell cycle arrest, and ultimately, cell death. It has also been demonstrated that Ran dysregulation influences nucleocytoplasmic transport, leading to transcription factor misallocation. Consequently, patients with tumors that overexpress Ran have been shown to have a higher malignancy rate and a shorter survival time compared to their counterparts.
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Affiliation(s)
- Mohamed El-Tanani
- Pharmacological and Diagnostic Research Centre, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan
| | - Hamdi Nsairat
- Pharmacological and Diagnostic Research Centre, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan
| | - Vijay Mishra
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara 144411, India
| | - Yachana Mishra
- Department of Zoology, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara 144411, India
| | - Alaa A. A. Aljabali
- Department of Pharmaceutics & Pharmaceutical Technology, Yarmouk University, Irbid 21163, Jordan
| | - Ángel Serrano-Aroca
- Biomaterials and Bioengineering Laboratory, Centro de Investigación Traslacional San Alberto Magno, Universidad Católica de Valencia San Vicente Mártir, c/Guillem de Castro 94, 46001 Valencia, Spain
| | - Murtaza M. Tambuwala
- Lincoln Medical School, University of Lincoln, Brayford Pool, Lincoln LN6 7TS, UK
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20
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Yang M, Li M, Lyu Z, Yang Z. Implication of Ferroptosis in Cholangiocarcinoma: A Potential Future Target? Cancer Manag Res 2023; 15:335-342. [PMID: 37063167 PMCID: PMC10093512 DOI: 10.2147/cmar.s406150] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 03/30/2023] [Indexed: 04/18/2023] Open
Abstract
Cholangiocarcinoma (CCA), the second most common liver neoplasm, has a poor overall 5-year survival rate of less than 10%. A deeper understanding of the molecular pathogenesis contributing to CCA progression is essential for developing better therapeutic approaches to manage this disease. Ferroptosis, an oxidative iron-dependent form of regulated cell death, has been reported to be involved in tumorigenesis and progression. In particular, ferroptosis and inflammation, which are common issues in cholangiocarcinogenesis and CCA development, might be in concert with disease progression. Notably, the key feature of cancer cells is "iron addiction", which is crucial for the high metabolic demand in carcinogenesis and cancer progression. Additionally, iron metabolism is of great importance in ferroptosis. Moreover, that cancer cells are vulnerable to ferroptosis might be a possible mechanism of CCA development. Although the underlying mechanism of how ferroptosis is implicated in CCA development requires further investigation, developing a new strategy combined with a pro-ferroptotic treatment would be an exciting CCA treatment approach in the future.
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Affiliation(s)
- Mingyu Yang
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 25000, People’s Republic of China
| | - Meng Li
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 25000, People’s Republic of China
| | - Zhuozhen Lyu
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 25000, People’s Republic of China
| | - Zhen Yang
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 25000, People’s Republic of China
- Correspondence: Zhen Yang, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, JingWu Road, Jinan, Shandong, 25000, People’s Republic of China, Tel +86 15168867123, Email
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21
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Duan G, Li J, Duan Y, Zheng C, Guo Q, Li F, Zheng J, Yu J, Zhang P, Wan M, Long C. Mitochondrial Iron Metabolism: The Crucial Actors in Diseases. Molecules 2022; 28:29. [PMID: 36615225 PMCID: PMC9822237 DOI: 10.3390/molecules28010029] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 12/12/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022] Open
Abstract
Iron is a trace element necessary for cell growth, development, and cellular homeostasis, but insufficient or excessive level of iron is toxic. Intracellularly, sufficient amounts of iron are required for mitochondria (the center of iron utilization) to maintain their normal physiologic function. Iron deficiency impairs mitochondrial metabolism and respiratory activity, while mitochondrial iron overload promotes ROS production during mitochondrial electron transport, thus promoting potential disease development. This review provides an overview of iron homeostasis, mitochondrial iron metabolism, and how mitochondrial iron imbalances-induced mitochondrial dysfunction contribute to diseases.
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Affiliation(s)
- Geyan Duan
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jianjun Li
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yehui Duan
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Changbing Zheng
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Qiuping Guo
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Fengna Li
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jie Zheng
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jiayi Yu
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Peiwen Zhang
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Mengliao Wan
- College of Animal Science and Technology, Hunan Agricultural University, Changsha 410128, China
| | - Cimin Long
- CAS Key Laboratory of Agro-Ecological Processes in Subtropical Region, Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
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22
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Bronchoalveolar Lavage Fluid-Isolated Biomarkers for the Diagnostic and Prognostic Assessment of Lung Cancer. Diagnostics (Basel) 2022; 12:diagnostics12122949. [PMID: 36552956 PMCID: PMC9776496 DOI: 10.3390/diagnostics12122949] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/18/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022] Open
Abstract
Lung cancer is considered one of the most fatal malignant neoplasms because of its late detection. Detecting molecular markers in samples from routine bronchoscopy, including many liquid-based cytology procedures, such as bronchoalveolar lavage fluid (BALF), could serve as a favorable technique to enhance the efficiency of a lung cancer diagnosis. BALF analysis is a promising approach to evaluating the tumor progression microenvironment. BALF's cellular and non-cellular components dictate the inflammatory response in a cancer-proliferating microenvironment. Furthermore, it is an essential material for detecting clinically significant predictive and prognostic biomarkers that may aid in guiding treatment choices and evaluating therapy-induced toxicities in lung cancer. In the present article, we have reviewed recent literature about the utility of BALF analysis for detecting markers in different stages of tumor cell metabolism, employing either specific biomarker assays or broader omics approaches.
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23
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New Iron Metabolic Pathways and Chelation Targeting Strategies Affecting the Treatment of All Types and Stages of Cancer. Int J Mol Sci 2022; 23:ijms232213990. [PMID: 36430469 PMCID: PMC9696688 DOI: 10.3390/ijms232213990] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/02/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
There is new and increasing evidence from in vitro, in vivo and clinical studies implicating the pivotal role of iron and associated metabolic pathways in the initiation, progression and development of cancer and in cancer metastasis. New metabolic and toxicity mechanisms and pathways, as well as genomic, transcription and other factors, have been linked to cancer and many are related to iron. Accordingly, a number of new targets for iron chelators have been identified and characterized in new anticancer strategies, in addition to the classical restriction of/reduction in iron supply, the inhibition of transferrin iron delivery, the inhibition of ribonucleotide reductase in DNA synthesis and high antioxidant potential. The new targets include the removal of excess iron from iron-laden macrophages, which affects anticancer activity; the modulation of ferroptosis; ferritin iron removal and the control of hyperferritinemia; the inhibition of hypoxia related to the role of hypoxia-inducible factor (HIF); modulation of the function of new molecular species such as STEAP4 metalloreductase and the metastasis suppressor N-MYC downstream-regulated gene-1 (NDRG1); modulation of the metabolic pathways of oxidative stress damage affecting mitochondrial function, etc. Many of these new, but also previously known associated iron metabolic pathways appear to affect all stages of cancer, as well as metastasis and drug resistance. Iron-chelating drugs and especially deferiprone (L1), has been shown in many recent studies to fulfill the role of multi-target anticancer drug linked to the above and also other iron targets, and has been proposed for phase II trials in cancer patients. In contrast, lipophilic chelators and their iron complexes are proposed for the induction of ferroptosis in some refractory or recurring tumors in drug resistance and metastasis where effective treatments are absent. There is a need to readdress cancer therapy and include therapeutic strategies targeting multifactorial processes, including the application of multi-targeting drugs involving iron chelators and iron-chelator complexes. New therapeutic protocols including drug combinations with L1 and other chelating drugs could increase anticancer activity, decrease drug resistance and metastasis, improve treatments, reduce toxicity and increase overall survival in cancer patients.
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24
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Abdelaal G, Carter A, Panayiotides MI, Tetard D, Veuger S. Novel iron chelator SK4 demonstrates cytotoxicity in a range of tumour derived cell lines. Front Mol Biosci 2022; 9:1005092. [PMID: 36213122 PMCID: PMC9540520 DOI: 10.3389/fmolb.2022.1005092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 08/22/2022] [Indexed: 11/24/2022] Open
Abstract
Iron is an essential micronutrient due to its involvement in many cellular processes including DNA replication and OXPHOS. Tumors overexpress iron metabolism linked proteins which allow for iron accumulation driving high levels of proliferation. Our group has designed novel iron chelator SK4 which targets cancer’s “iron addiction.” SK4 comprises of two key moieties: an iron chelation moiety responsible for cytotoxicity and an amino acid moiety which allows entry through amino acid transporter LAT1. We selected LAT1 as a route of entry as it is commonly overexpressed in malignant tumors. SK4 has previously demonstrated promising results in an in vitro model for melanoma. We hypothesized SK4 would be effective against a range of tumor types. We have screened a panel of tumor-derived cell lines from different origins including breast, prostate, ovarian and cervical cancer for SK4 sensitivity and we have found a range of differential sensitivities varying from 111.3 to >500 μM. We validated the iron chelation moiety as responsible for inducing cytotoxicity through control compounds; each lacking a key moiety. Following the screen, we conducted a series of assays to elucidate the mechanism of action behind SK4 cytotoxicity. SK4 was shown to induce apoptosis in triple negative breast cancer cell line MDA MB 231 but not ovarian cancer cell line SKOV3 suggesting SK4 may induce different modes of cell death in each cell line. As MDA MB 231 cells harbor a mutation in p53, we conclude SK4 is capable of inducing apoptosis in a p53-independent manner. SK4 upregulated NDRG1 expression in MDA MB 231 and SKOV3 cells. Interestingly, knockdown of NDRG1 antagonized SK4 in MDA MB 231 cells but not SKOV3 cells suggesting SK4’s mechanism of action may be mediated through NDRG1 in MDA MB 231 cells. In conclusion, we have shown tagging iron chelators with an amino acid moiety to allow entry through the LAT1 transporter represents a double pronged approach to cancer therapy, targeting “iron addiction” and amino acid metabolism dysregulation.
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Affiliation(s)
- Gina Abdelaal
- Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom
- *Correspondence: Gina Abdelaal, ; Stephany Veuger,
| | - Andrew Carter
- Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom
| | - Mihalis I. Panayiotides
- Department of Cancer Genetics, Therapeutics and Ultrastructural Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
| | - David Tetard
- Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom
| | - Stephany Veuger
- Department of Applied Sciences, Faculty of Health and Life Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom
- *Correspondence: Gina Abdelaal, ; Stephany Veuger,
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25
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Kabil MF, Mahmoud MY, Bakr AF, Zaafar D, El-Sherbiny IM. Switching indication of PEGylated lipid nanocapsules-loaded with rolapitant and deferasirox against breast cancer: Enhanced in-vitro and in-vivo cytotoxicity. Life Sci 2022; 305:120731. [PMID: 35753435 DOI: 10.1016/j.lfs.2022.120731] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/11/2022] [Accepted: 06/20/2022] [Indexed: 12/12/2022]
Abstract
Breast cancer (BC) is considered the leading cause of mortality and morbidity among adult women worldwide, and it is associated with many genetic or hormonal factors. Despite the advanced therapeutic and theranostic strategies for BC treatment, cancer metastasis and relapse are often observed among patients which lead to therapeutic failure. Accordingly, among the repositioned medication against BC proliferation is neurokinin receptor antagonists and iron chelating agents especially rolapitant HCl (RP) and deferasirox (DFO), respectively. However, RP and DFO are classified as class II with low aqueous solubility. Both drugs were nanoformulated into PEGylated lipid nanocapsules (LNCs) for enhancing their aqueous solubility and augmenting their efficacy. RP-LNCs, DFO-LNCs and their combinations were evaluated according to particle size (PS), zeta potential, polydispersity index (PDI) and surface morphology. Importantly, the antitumor effect of these novel molecules and their nanoforms was evaluated against the suppression of Ehrlich Ascites tumor model using female mice. Results revealed that RP-LNCs, DFO-LNCs and RP/DFO-LNCs exerted PS from 45.23 ± 3.54 to 60.1 ± 3.32 nm with PDI around 0.20 which indicates homogenous particles distribution. Also, RP-LNCs, DFO-LNCs and RP/DFO-LNCs displayed surface charges of +16.6 ± 6.9, -13.3 ± 5.82 and - 20.2 ± 5.40 mV, respectively. The obtained LNCs conferred a high potent cytotoxic effect against MCF7 cancer cells as compared to parent drugs, with IC50 of 10.86 ± 0.89, 3.34 ± 0.99 and 2.24 ± 0.97 μg/mL for RP-LNCs, DFO-LNCs and RP/DFO-LNCs, respectively. The in-vivo pharmacodynamics effect of the developed nano-formulations showed superior antitumor effect for the individual drugs rather than their combinations as compared to the control group. The current study confirmed the potential of RP and DFO nanoforms as promising therapeutic agents for BC treatment.
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Affiliation(s)
- Mohamed Fawzi Kabil
- Nanomedicine Research Labs, Center for Materials Science, Zewail City of Science and Technology, 6th of October City, Giza, Egypt
| | - Mohamed Y Mahmoud
- Department of Toxicology and Forensic Medicine, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Alaa F Bakr
- Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Dalia Zaafar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Ibrahim M El-Sherbiny
- Nanomedicine Research Labs, Center for Materials Science, Zewail City of Science and Technology, 6th of October City, Giza, Egypt.
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26
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Krchniakova M, Paukovcekova S, Chlapek P, Neradil J, Skoda J, Veselska R. Thiosemicarbazones and selected tyrosine kinase inhibitors synergize in pediatric solid tumors: NDRG1 upregulation and impaired prosurvival signaling in neuroblastoma cells. Front Pharmacol 2022; 13:976955. [PMID: 36160437 PMCID: PMC9490180 DOI: 10.3389/fphar.2022.976955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/01/2022] [Indexed: 11/21/2022] Open
Abstract
Tyrosine kinase inhibitors (TKIs) are frequently used in combined therapy to enhance treatment efficacy and overcome drug resistance. The present study analyzed the effects of three inhibitors, sunitinib, gefitinib, and lapatinib, combined with iron-chelating agents, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) or di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC). Simultaneous administration of the drugs consistently resulted in synergistic and/or additive activities against the cell lines derived from the most frequent types of pediatric solid tumors. The results of a detailed analysis of cell signaling in the neuroblastoma cell lines revealed that TKIs inhibited the phosphorylation of the corresponding receptor tyrosine kinases, and thiosemicarbazones downregulated the expression of epidermal growth factor receptor, platelet-derived growth factor receptor, and insulin-like growth factor-1 receptor, leading to a strong induction of apoptosis. Marked upregulation of the metastasis suppressor N-myc downstream regulated gene-1 (NDRG1), which is known to be activated and upregulated by thiosemicarbazones in adult cancers, was also detected in thiosemicarbazone-treated neuroblastoma cells. Importantly, these effects were more pronounced in the cells treated with drug combinations, especially with the combinations of lapatinib with thiosemicarbazones. Therefore, these results provide a rationale for novel strategies combining iron-chelating agents with TKIs in therapy of pediatric solid tumors.
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Affiliation(s)
- Maria Krchniakova
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czechia
- International Clinical Research Center, St. Anne’s University Hospital, Brno, Czechia
| | - Silvia Paukovcekova
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czechia
| | - Petr Chlapek
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czechia
- International Clinical Research Center, St. Anne’s University Hospital, Brno, Czechia
| | - Jakub Neradil
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czechia
- International Clinical Research Center, St. Anne’s University Hospital, Brno, Czechia
| | - Jan Skoda
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czechia
- International Clinical Research Center, St. Anne’s University Hospital, Brno, Czechia
- *Correspondence: Jan Skoda, ; Renata Veselska,
| | - Renata Veselska
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czechia
- International Clinical Research Center, St. Anne’s University Hospital, Brno, Czechia
- *Correspondence: Jan Skoda, ; Renata Veselska,
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27
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Abedi M, Rahgozar S. Puzzling Out Iron Complications in Cancer Drug Resistance. Crit Rev Oncol Hematol 2022; 178:103772. [PMID: 35914667 DOI: 10.1016/j.critrevonc.2022.103772] [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: 05/28/2022] [Revised: 07/23/2022] [Accepted: 07/28/2022] [Indexed: 12/09/2022] Open
Abstract
Iron metabolism are frequently disrupted in cancer. Patients with cancer are prone to anemia and receive transfusions frequently; the condition which results in iron overload, contributing to serious therapeutic complications. Iron is introduced as a carcinogen that may increase tumor growth. However, investigations regarding its impact on response to chemotherapy, particularly the induction of drug resistance are still limited. Here, iron contribution to cell signaling and various molecular mechanisms underlying iron-mediated drug resistance are described. A dual role of this vital element in cancer treatment is also addressed. On one hand, the need to administer iron chelators to surmount iron overload and improve the sensitivity of tumor cells to chemotherapy is discussed. On the other hand, the necessary application of iron as a therapeutic option by iron-oxide nanoparticles or ferroptosis inducers is explained. Authors hope that this paper can help unravel the clinical complications related to iron in cancer therapy.
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Affiliation(s)
- Marjan Abedi
- Department of Cell and Molecular biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
| | - Soheila Rahgozar
- Department of Cell and Molecular biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
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28
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KAYA B. An Iron(III)-S-methylthiosemicarbazone Complex: Synthesis, Spectral Characterization, and Antioxidant Potency Measured by CUPRAC and DPPH Methods. JOURNAL OF THE TURKISH CHEMICAL SOCIETY, SECTION A: CHEMISTRY 2022. [DOI: 10.18596/jotcsa.1058398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
An iron(III) complex, [Fe(L1)Cl].H2O, was synthesized by template condensation reaction of 1,1,1-Trifluoroacetylacetone-S-methylthiosemicarbazone hydrogen iodide (L) and 2,3-dihydroxybenzaldehyde in the presence of iron(III) ions. The complex was characterized by IR, ESI MS and X-ray diffraction techniques. Free radical scavenging (FRS) ability and antioxidant capacity of the S-methylthiosemicarbazone and the iron(III) complex were evaluated through DPPH and CUPRAC methods, respectively. The complex exerted better than the S-methylthiosemicarbazone in both TEAC and FRS% values. In addition, iron(III) complex was found to be 3.1 times more antioxidant than the reference ascorbic acid according to the CUPRAC method.
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Affiliation(s)
- Büşra KAYA
- İSTANBUL ÜNİVERSİTESİ-CERRAHPAŞA, MÜHENDİSLİK FAKÜLTESİ
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29
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Fujisawa K, Takami T, Matsumoto T, Yamamoto N, Yamasaki T, Sakaida I. An iron chelation-based combinatorial anticancer therapy comprising deferoxamine and a lactate excretion inhibitor inhibits the proliferation of cancer cells. Cancer Metab 2022; 10:8. [PMID: 35550011 PMCID: PMC9103045 DOI: 10.1186/s40170-022-00284-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 04/04/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Although iron chelation has garnered attention as a novel therapeutic strategy for cancer, higher levels of efficacy need to be achieved. In the present study, we examined the combinatorial effect of deferoxamine (DFO), an iron chelator, and α-cyano-4-hydroxy cinnamate (CHC), a suppressor of lactate excretion, on the proliferation of cancer cell lines. METHODS We established a deferoxamine (DFO)-resistant cell line by culturing HeLa cells in media containing increasing concentrations of DFO. Metabolome and gene expression analyses were performed on these cells. Synergistic effect of the drugs on the cells was determined using an in vitro proliferation assay, and the combination index was estimated. RESULTS DFO-resistant HeLa cells exhibited enhanced glycolysis, salvage cycle, and de novo nucleic acid synthesis and reduced mitochondrial metabolism. As DFO triggered a metabolic shift toward glycolysis and increased lactate production in cells, we treated the cancer cell lines with a combination of CHC and DFO. A synergistic effect of DFO and CHC was observed in HeLa cells; however, the same was not observed in the human liver cancer cell line Huh7. We hypothesized that the efficacy of the combination therapy in cancer cells depends on the degree of increase in lactate concentration upon DFO treatment. CONCLUSION Combination therapy involving administration of DFO and CHC is effective in cancer cells wherein DFO treatment results in an elevation in lactate levels. Our findings illustrate that the DFO-induced enhanced glycolysis provides specific targets for developing an efficient anticancer combinatorial therapy involving DFO. These findings will be beneficial for the development of novel cancer chemotherapeutics.
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Affiliation(s)
- Koichi Fujisawa
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami Kogushi 1-1-1, Ube, Yamaguchi, 755-8505, Japan
- Department of Environmental Oncology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, 807-8555, Japan
| | - Taro Takami
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami Kogushi 1-1-1, Ube, Yamaguchi, 755-8505, Japan.
| | - Toshihiko Matsumoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami Kogushi 1-1-1, Ube, Yamaguchi, 755-8505, Japan
- Department of Oncology and Laboratory Medicine, Graduate School of Medicine, Yamaguchi University, Minami Kogushi 1-1-1, Ube, Yamaguchi, Japan
| | - Naoki Yamamoto
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami Kogushi 1-1-1, Ube, Yamaguchi, 755-8505, Japan
- Yamaguchi University Health Administration Center, Yamaguchi, Japan
| | - Takahiro Yamasaki
- Department of Oncology and Laboratory Medicine, Graduate School of Medicine, Yamaguchi University, Minami Kogushi 1-1-1, Ube, Yamaguchi, Japan
| | - Isao Sakaida
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Minami Kogushi 1-1-1, Ube, Yamaguchi, 755-8505, Japan
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Supplementation with High or Low Iron Reduces Colitis Severity in an AOM/DSS Mouse Model. Nutrients 2022; 14:nu14102033. [PMID: 35631174 PMCID: PMC9147005 DOI: 10.3390/nu14102033] [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: 04/07/2022] [Revised: 05/03/2022] [Accepted: 05/07/2022] [Indexed: 11/17/2022] Open
Abstract
The relationship between colitis-associated colorectal cancer (CAC) and the dysregulation of iron metabolism has been implicated. However, studies on the influence of dietary iron deficiency on the incidence of CAC are limited. This study investigated the effects of dietary iron deficiency and dietary non-heme iron on CAC development in an azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model. The four-week-old mice were divided into the following groups: iron control (IC; 35 ppm iron/kg) + normal (NOR), IC + AOM/DSS, iron deficient (ID; <5 ppm iron/kg diet) + AOM/DSS, and iron overload (IOL; approximately 2000 ppm iron/kg) + AOM/DSS. The mice were fed the respective diets for 13 weeks, and the AOM/DSS model was established at week five. FTH1 expression increased in the mice’s colons in the IC + AOM/DSS group compared with that observed in the ID and IOL + AOM/DSS groups. The reduced number of colonic tumors in the ID + AOM/DSS and IOL + AOM/DSS groups was accompanied by the downregulated expression of cell proliferation regulators (PCNA, cyclin D1, and c-Myc). Iron overload inhibited the increase in the expression of NF-κB and its downstream inflammatory cytokines (IL-6, TNFα, iNOS, COX2, and IL-1β), likely due to the elevated expression of antioxidant genes (SOD1, TXN, GPX1, GPX4, CAT, HMOX1, and NQO1). ID + AOM/DSS may hinder tumor development in the AOM/DSS model by inhibiting the PI3K/AKT pathway by increasing the expression of Ndrg1. Our study suggests that ID and IOL diets suppress AOM/DSS-induced tumors and that long-term iron deficiency or overload may negate CAC progression.
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Si C, Zhou X, Deng J, Ye S, Kong L, Zhang B, Wang W. Role of ferroptosis in gastrointestinal tumors: From mechanisms to therapies. Cell Biol Int 2022; 46:997-1008. [PMID: 35476364 DOI: 10.1002/cbin.11804] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 02/16/2022] [Accepted: 03/24/2022] [Indexed: 01/01/2023]
Abstract
Ferroptosis is an iron-dependent nonapoptotic regulated cell death, which is mainly caused by an abnormal increase in lipid oxygen free radicals and an imbalance in redox homeostasis. Recently, ferroptosis has been shown to have implications in various gastrointestinal cancers, such as gastric carcinoma, hepatocellular carcinoma, and pancreatic cancer. This review summarises the latest research on ferroptosis, its mechanism of action, and its role in the progression of different gastrointestinal tumors to provide more information regarding the prevention and treatment of these tumors.
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Affiliation(s)
- Chenli Si
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Xiang Zhou
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jie Deng
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Shijie Ye
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Lingming Kong
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Baofu Zhang
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Weiming Wang
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
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Levina A, Crans DC, Lay PA. Advantageous Reactivity of Unstable Metal Complexes: Potential Applications of Metal-Based Anticancer Drugs for Intratumoral Injections. Pharmaceutics 2022; 14:790. [PMID: 35456624 PMCID: PMC9026487 DOI: 10.3390/pharmaceutics14040790] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/24/2022] [Accepted: 03/29/2022] [Indexed: 11/30/2022] Open
Abstract
Injections of highly cytotoxic or immunomodulating drugs directly into the inoperable tumor is a procedure that is increasingly applied in the clinic and uses established Pt-based drugs. It is advantageous for less stable anticancer metal complexes that fail administration by the standard intravenous route. Such hydrophobic metal-containing complexes are rapidly taken up into cancer cells and cause cell death, while the release of their relatively non-toxic decomposition products into the blood has low systemic toxicity and, in some cases, may even be beneficial. This concept was recently proposed for V(V) complexes with hydrophobic organic ligands, but it can potentially be applied to other metal complexes, such as Ti(IV), Ga(III) and Ru(III) complexes, some of which were previously unsuccessful in human clinical trials when administered via intravenous injections. The potential beneficial effects include antidiabetic, neuroprotective and tissue-regenerating activities for V(V/IV); antimicrobial activities for Ga(III); and antimetastatic and potentially immunogenic activities for Ru(III). Utilizing organic ligands with limited stability under biological conditions, such as Schiff bases, further enhances the tuning of the reactivities of the metal complexes under the conditions of intratumoral injections. However, nanocarrier formulations are likely to be required for the delivery of unstable metal complexes into the tumor.
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Affiliation(s)
- Aviva Levina
- School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia
| | - Debbie C. Crans
- Department of Chemistry and the Cell and Molecular Biology Program, Colorado State University, Fort Collins, CO 80523, USA
| | - Peter A. Lay
- School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia
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33
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Molecular mechanisms of reactive oxygen species in regulated cell deaths: Impact of ferroptosis in cancer therapy. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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34
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Guo Y, Li Y, Li J, Tao W, Dong W. DNA Methylation-Driven Genes for Developing Survival Nomogram for Low-Grade Glioma. Front Oncol 2022; 11:629521. [PMID: 35111661 PMCID: PMC8801588 DOI: 10.3389/fonc.2021.629521] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 12/20/2021] [Indexed: 12/13/2022] Open
Abstract
Low-grade gliomas (LGG) are heterogeneous, and the current predictive models for LGG are either unsatisfactory or not user-friendly. The objective of this study was to establish a nomogram based on methylation-driven genes, combined with clinicopathological parameters for predicting prognosis in LGG. Differential expression, methylation correlation, and survival analysis were performed in 516 LGG patients using RNA and methylation sequencing data, with accompanying clinicopathological parameters from The Cancer Genome Atlas. LASSO regression was further applied to select optimal prognosis-related genes. The final prognostic nomogram was implemented together with prognostic clinicopathological parameters. The predictive efficiency of the nomogram was internally validated in training and testing groups, and externally validated in the Chinese Glioma Genome Atlas database. Three DNA methylation-driven genes, ARL9, CMYA5, and STEAP3, were identified as independent prognostic factors. Together with IDH1 mutation status, age, and sex, the final prognostic nomogram achieved the highest AUC value of 0.930, and demonstrated stable consistency in both internal and external validations. The prognostic nomogram could predict personal survival probabilities for patients with LGG, and serve as a user-friendly tool for prognostic evaluation, optimizing therapeutic regimes, and managing LGG patients.
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Affiliation(s)
- Yingyun Guo
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yuan Li
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jiao Li
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Weiping Tao
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Weiguo Dong
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
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35
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Macsek P, Skoda J, Krchniakova M, Neradil J, Veselska R. Iron-Chelation Treatment by Novel Thiosemicarbazone Targets Major Signaling Pathways in Neuroblastoma. Int J Mol Sci 2021; 23:ijms23010376. [PMID: 35008802 PMCID: PMC8745636 DOI: 10.3390/ijms23010376] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 12/24/2021] [Accepted: 12/27/2021] [Indexed: 01/23/2023] Open
Abstract
Despite constant advances in the field of pediatric oncology, the survival rate of high-risk neuroblastoma patients remains poor. The molecular and genetic features of neuroblastoma, such as MYCN amplification and stemness status, have established themselves not only as potent prognostic and predictive factors but also as intriguing targets for personalized therapy. Novel thiosemicarbazones target both total level and activity of a number of proteins involved in some of the most important signaling pathways in neuroblastoma. In this study, we found that di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) potently decreases N-MYC in MYCN-amplified and c-MYC in MYCN-nonamplified neuroblastoma cell lines. Furthermore, DpC succeeded in downregulating total EGFR and phosphorylation of its most prominent tyrosine residues through the involvement of NDRG1, a positive prognostic marker in neuroblastoma, which was markedly upregulated after thiosemicarbazone treatment. These findings could provide useful knowledge for the treatment of MYC-driven neuroblastomas that are unresponsive to conventional therapies.
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Affiliation(s)
- Peter Macsek
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, 601 77 Brno, Czech Republic; (P.M.); (J.S.); (M.K.); (R.V.)
- International Clinical Research Center, St. Anne’s University Hospital, 656 91 Brno, Czech Republic
| | - Jan Skoda
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, 601 77 Brno, Czech Republic; (P.M.); (J.S.); (M.K.); (R.V.)
- International Clinical Research Center, St. Anne’s University Hospital, 656 91 Brno, Czech Republic
| | - Maria Krchniakova
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, 601 77 Brno, Czech Republic; (P.M.); (J.S.); (M.K.); (R.V.)
| | - Jakub Neradil
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, 601 77 Brno, Czech Republic; (P.M.); (J.S.); (M.K.); (R.V.)
- International Clinical Research Center, St. Anne’s University Hospital, 656 91 Brno, Czech Republic
- Department of Pediatric Oncology, Faculty of Medicine, University Hospital Brno, Masaryk University, 662 63 Brno, Czech Republic
- Correspondence: ; Tel.: +420-549-49-6003
| | - Renata Veselska
- Laboratory of Tumor Biology, Department of Experimental Biology, Faculty of Science, Masaryk University, 601 77 Brno, Czech Republic; (P.M.); (J.S.); (M.K.); (R.V.)
- International Clinical Research Center, St. Anne’s University Hospital, 656 91 Brno, Czech Republic
- Department of Pediatric Oncology, Faculty of Medicine, University Hospital Brno, Masaryk University, 662 63 Brno, Czech Republic
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Guo Q, Li L, Hou S, Yuan Z, Li C, Zhang W, Zheng L, Li X. The Role of Iron in Cancer Progression. Front Oncol 2021; 11:778492. [PMID: 34858857 PMCID: PMC8631356 DOI: 10.3389/fonc.2021.778492] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 10/15/2021] [Indexed: 01/19/2023] Open
Abstract
Iron is an essential trace element for the human body, and its deficiency or excess can induce a variety of biological processes. Plenty of evidences have shown that iron metabolism is closely related to the occurrence and development of tumors. In addition, iron plays an important role in cell death, which is very important for the development of potential strategies for tumor treatment. Here, we reviewed the latest research about iron metabolism disorders in various types of tumors, the functions and properties of iron in ferroptosis and ferritinophagy, and new opportunities for iron-based on treatment methods for tumors, providing more information regarding the prevention and treatment of tumors.
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Affiliation(s)
- Qianqian Guo
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Liwen Li
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Shanshan Hou
- Department of Pharmacy, Zhejiang Pharmaceutical College, Ningbo, China
| | - Ziqiao Yuan
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
| | - Chenhui Li
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Wenzhou Zhang
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaoman Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
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Ramírez-Carmona W, Díaz-Fabregat B, Yuri Yoshigae A, Musa de Aquino A, Scarano WR, de Souza Castilho AC, Avansini Marsicano J, Leal do Prado R, Pessan JP, de Oliveira Mendes L. Are Serum Ferritin Levels a Reliable Cancer Biomarker? A Systematic Review and Meta-Analysis. Nutr Cancer 2021; 74:1917-1926. [PMID: 34607491 DOI: 10.1080/01635581.2021.1982996] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Although serum ferritin (SF) has been shown in several studies to be a potential cancer biomarker, the results are inconsistent. Herein, a systematic review was performed to investigate the clinical SF levels in different types of tumors in order to verify the role of SF levels as a biomarker for cancer diagnosis. The search was performed using the PubMed/Medline, Cochrane Library, and Scopus databases. Observational studies comparing SF levels between healthy adults and patients with cancer were included. The meta-analysis was carried out according to the inverse variance and random effects model. The standardized mean differences (SMDs) were assessed at 95% confidence intervals (CIs). We found that SF was higher in patients with cancer (SMD 3.07; CI 1.96,4.17), especially for head and neck cancer (SMD 3.88; CI 0.42,7.34), lung cancer (SMD 1.72; CI 0.67,2.78), pancreatic cancer (SMD 6.79; CI 5.66,7.91), and renal cell carcinoma (SMD 1.77; CI 0.48,3.05). Moreover, in the advanced stages (Stages III and IV), ferritin levels were higher than in healthy adults (SMD 4.89; CI 2.72,7.06, and SMD 8.40; CI 6.99,9.82, respectively). SF acts as a biomarker for pancreatic cancer, renal cell carcinoma, lung cancer, and head and neck cancer and is a sensitive biomarker for the detection of advanced stages of tumors.
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Affiliation(s)
| | - Beatriz Díaz-Fabregat
- Department of Pediatric Dentistry and Public Heatlhy, Araçatuba Dental School, Univ. Estadual Paulista (UNESP), Araçatuba, SP, Brazil
| | | | - Ariana Musa de Aquino
- Department of Structural and Functional Biology, Institute of Biosciences, Univ. Estadual Paulista (UNESP), Botucatu, SP, Brazil
| | - Wellerson Rodrigo Scarano
- Department of Structural and Functional Biology, Institute of Biosciences, Univ. Estadual Paulista (UNESP), Botucatu, SP, Brazil
| | | | | | | | - Juliano Pelim Pessan
- Department of Pediatric Dentistry and Public Heatlhy, Araçatuba Dental School, Univ. Estadual Paulista (UNESP), Araçatuba, SP, Brazil
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Wang H, Lin D, Yu Q, Li Z, Lenahan C, Dong Y, Wei Q, Shao A. A Promising Future of Ferroptosis in Tumor Therapy. Front Cell Dev Biol 2021; 9:629150. [PMID: 34178977 PMCID: PMC8219969 DOI: 10.3389/fcell.2021.629150] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 04/26/2021] [Indexed: 12/24/2022] Open
Abstract
Currently, mechanisms and therapeutic approaches have been thoroughly studied in various prevalent malignant tumors, such as breast and lung cancer. However, there is inevitable tumor progression and drug resistance. Uncovering novel treatment strategies to inhibit tumor development is important. Ferroptosis, a form of cell death associated with iron and lipid peroxidation, has drawn extensive attention. In this paper, we reviewed the underlying mechanisms of ferroptosis (i.e., iron, glutathione, and lipid metabolism) and its role in various tumors (i.e., lung cancer, liver carcinoma, breast cancer, and pancreatic cancer). Moreover, we summarized ferroptosis-related anti-tumor drugs and emphasized the potential of combined treatment of anti-tumor drugs and radiotherapy in an effort to provide novel anti-tumor treatments.
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Affiliation(s)
- Hui Wang
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Danfeng Lin
- Department of Breast Surgery, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qianqian Yu
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhouqi Li
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Cameron Lenahan
- Burrell College of Osteopathic Medicine, Las Cruces, NM, United States
- Center for Neuroscience Research, Loma Linda University School of Medicine, Loma Linda, CA, United States
| | - Ying Dong
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qichun Wei
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Anwen Shao
- Department of Neurosurgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Roemhild K, von Maltzahn F, Weiskirchen R, Knüchel R, von Stillfried S, Lammers T. Iron metabolism: pathophysiology and pharmacology. Trends Pharmacol Sci 2021; 42:640-656. [PMID: 34090703 DOI: 10.1016/j.tips.2021.05.001] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 04/23/2021] [Accepted: 05/06/2021] [Indexed: 01/19/2023]
Abstract
Iron is essential in many physiological processes, including DNA metabolism, oxygen transport, and cellular energy generation. Deregulated iron metabolism, which results in iron overload or iron deficiency, is observed in many different diseases. We here summarize recent progress in the pathophysiology and pharmacology of iron-overload diseases, such as hereditary hemochromatosis, as well as iron-deficiency disorders, which are typically associated with anemia. The role of iron in immunity and the connection between iron and cancer are also addressed. We finally summarize and discuss the current (pre-) clinical landscape of pharmacotherapies targeting key players involved in iron metabolism.
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Affiliation(s)
- Karolin Roemhild
- Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, RWTH University Hospital Aachen, Aachen 52074, Germany; Institute of Pathology, Medical Faculty, RWTH University Hospital Aachen, Aachen 52074, Germany
| | - Finn von Maltzahn
- Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, RWTH University Hospital Aachen, Aachen 52074, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen 52074, Germany
| | - Ruth Knüchel
- Institute of Pathology, Medical Faculty, RWTH University Hospital Aachen, Aachen 52074, Germany
| | - Saskia von Stillfried
- Institute of Pathology, Medical Faculty, RWTH University Hospital Aachen, Aachen 52074, Germany
| | - Twan Lammers
- Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, RWTH University Hospital Aachen, Aachen 52074, Germany.
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40
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Liao HY, Liao B, Zhang HH. CISD2 plays a role in age-related diseases and cancer. Biomed Pharmacother 2021; 138:111472. [PMID: 33752060 DOI: 10.1016/j.biopha.2021.111472] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 03/03/2021] [Accepted: 03/04/2021] [Indexed: 12/12/2022] Open
Abstract
CDGSH iron-sulfur domain 2 (Cisd2) is an evolutionarily conserved protein that plays an important regulatory role in aging-related diseases and cancers. Since its discovery, Cisd2 has been identified as a regulatory factor for the aging of the human body and the regulation of mammalian lifespan. Cisd2 is also an oncoprotein that regulates the occurrence and development of cancer. Cisd2 mediates the occurrence of diseases related to human aging and the proliferation, differentiation, metastasis, and invasion of various cancer cells through various mechanisms. Multiple studies have shown that Cisd2 expression is related to the clinical characteristics of aging-related diseases and patients with cancer, and its expression profile is a novel diagnostic and prognostic biomarker for a variety of human diseases. Modulating the expression or function of Cisd2 may be a potential treatment strategy for different diseases. In this review, we summarize the role of Cisd2 in human aging-related diseases and various cancers, as well as the biological functions, underlying mechanisms, and potential clinical significance.
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Affiliation(s)
- Hai-Yang Liao
- The Second Clinical Medical College of Lanzhou University, 82 Cuiying Men, Lanzhou 730030, PR China; Orthopedics Key Laboratory of Gansu Province, Lanzhou 730000, PR China.
| | - Bei Liao
- Orthopedics Key Laboratory of Gansu Province, Lanzhou 730000, PR China; The First Clinical Medical College of Lanzhou University, 1 Donggang Road, Lanzhou 730000, PR China.
| | - Hai-Hong Zhang
- The Second Clinical Medical College of Lanzhou University, 82 Cuiying Men, Lanzhou 730030, PR China; Orthopedics Key Laboratory of Gansu Province, Lanzhou 730000, PR China.
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41
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Iron-Bound Lipocalin-2 from Tumor-Associated Macrophages Drives Breast Cancer Progression Independent of Ferroportin. Metabolites 2021; 11:metabo11030180. [PMID: 33808732 PMCID: PMC8003561 DOI: 10.3390/metabo11030180] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 03/12/2021] [Accepted: 03/16/2021] [Indexed: 01/12/2023] Open
Abstract
Macrophages supply iron to the breast tumor microenvironment by enforced secretion of lipocalin-2 (Lcn-2)-bound iron as well as the increased expression of the iron exporter ferroportin (FPN). We aimed at identifying the contribution of each pathway in supplying iron for the growing tumor, thereby fostering tumor progression. Analyzing the expression profiles of Lcn-2 and FPN using the spontaneous polyoma-middle-T oncogene (PyMT) breast cancer model as well as mining publicly available TCGA (The Cancer Genome Atlas) and GEO Series(GSE) datasets from the Gene Expression Omnibus database (GEO), we found no association between tumor parameters and Lcn-2 or FPN. However, stromal/macrophage-expression of Lcn-2 correlated with tumor onset, lung metastases, and recurrence, whereas FPN did not. While the total iron amount in wildtype and Lcn-2-/- PyMT tumors showed no difference, we observed that tumor-associated macrophages from Lcn-2-/- compared to wildtype tumors stored more iron. In contrast, Lcn-2-/- tumor cells accumulated less iron than their wildtype counterparts, translating into a low migratory and proliferative capacity of Lcn-2-/- tumor cells in a 3D tumor spheroid model in vitro. Our data suggest a pivotal role of Lcn-2 in tumor iron-management, affecting tumor growth. This study underscores the role of iron for tumor progression and the need for a better understanding of iron-targeted therapy approaches.
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Sandoval-Acuña C, Torrealba N, Tomkova V, Jadhav SB, Blazkova K, Merta L, Lettlova S, Adamcová MK, Rosel D, Brábek J, Neuzil J, Stursa J, Werner L, Truksa J. Targeting Mitochondrial Iron Metabolism Suppresses Tumor Growth and Metastasis by Inducing Mitochondrial Dysfunction and Mitophagy. Cancer Res 2021; 81:2289-2303. [PMID: 33685989 DOI: 10.1158/0008-5472.can-20-1628] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 11/20/2020] [Accepted: 03/01/2021] [Indexed: 11/16/2022]
Abstract
Deferoxamine (DFO) represents a widely used iron chelator for the treatment of iron overload. Here we describe the use of mitochondrially targeted deferoxamine (mitoDFO) as a novel approach to preferentially target cancer cells. The agent showed marked cytostatic, cytotoxic, and migrastatic properties in vitro, and it significantly suppressed tumor growth and metastasis in vivo. The underlying molecular mechanisms included (i) impairment of iron-sulfur [Fe-S] cluster/heme biogenesis, leading to destabilization and loss of activity of [Fe-S] cluster/heme containing enzymes, (ii) inhibition of mitochondrial respiration leading to mitochondrial reactive oxygen species production, resulting in dysfunctional mitochondria with markedly reduced supercomplexes, and (iii) fragmentation of the mitochondrial network and induction of mitophagy. Mitochondrial targeting of deferoxamine represents a way to deprive cancer cells of biologically active iron, which is incompatible with their proliferation and invasion, without disrupting systemic iron metabolism. Our findings highlight the importance of mitochondrial iron metabolism for cancer cells and demonstrate repurposing deferoxamine into an effective anticancer drug via mitochondrial targeting. SIGNIFICANCE: These findings show that targeting the iron chelator deferoxamine to mitochondria impairs mitochondrial respiration and biogenesis of [Fe-S] clusters/heme in cancer cells, which suppresses proliferation and migration and induces cell death. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2289/F1.large.jpg.
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Affiliation(s)
- Cristian Sandoval-Acuña
- Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Vestec, Czech Republic
| | - Natalia Torrealba
- Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Vestec, Czech Republic
| | - Veronika Tomkova
- Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Vestec, Czech Republic
| | - Sukanya B Jadhav
- Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Vestec, Czech Republic
| | - Kristyna Blazkova
- Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Vestec, Czech Republic
| | - Ladislav Merta
- Faculty of Sciences, BIOCEV Research Center, Charles University, Vestec, Czech Republic
| | - Sandra Lettlova
- Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Vestec, Czech Republic
| | - Miroslava K Adamcová
- Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Daniel Rosel
- Faculty of Sciences, BIOCEV Research Center, Charles University, Vestec, Czech Republic
| | - Jan Brábek
- Faculty of Sciences, BIOCEV Research Center, Charles University, Vestec, Czech Republic
| | - Jiri Neuzil
- Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Vestec, Czech Republic.,School of Medical Science, Griffith University, Southport, Queensland, Australia
| | - Jan Stursa
- Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Vestec, Czech Republic
| | - Lukas Werner
- Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Vestec, Czech Republic
| | - Jaroslav Truksa
- Institute of Biotechnology of the Czech Academy of Sciences, BIOCEV Research Center, Vestec, Czech Republic.
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Shen L, Zhou Y, He H, Chen W, Lenahan C, Li X, Deng Y, Shao A, Huang J. Crosstalk between Macrophages, T Cells, and Iron Metabolism in Tumor Microenvironment. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:8865791. [PMID: 33628389 PMCID: PMC7889336 DOI: 10.1155/2021/8865791] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 09/28/2020] [Accepted: 01/12/2021] [Indexed: 02/06/2023]
Abstract
Leukocytes, including macrophages and T cells, represent key players in the human immune system, which plays a considerable role in the development and progression of tumors by immune surveillance or immune escape. Boosting the recruitment of leukocytes into the tumor microenvironment and promoting their antitumor responses have been hot areas of research in recent years. Although immunotherapy has manifested a certain level of success in some malignancies, the overall effectiveness is far from satisfactory. Iron is an essential trace element required in multiple, normal cellular processes, such as DNA synthesis and repair, cellular respiration, metabolism, and signaling, while dysregulated iron metabolism has been declared one of the metabolic hallmarks of malignant cancer cells. Furthermore, iron is implicated in the modulation of innate and adaptive immune responses, and elucidating the targeted regulation of iron metabolism may have the potential to benefit antitumor immunity and cancer treatment. In the present review, we briefly summarize the roles of leukocytes and iron metabolism in tumorigenesis, as well as their crosstalk in the tumor microenvironment. The combination of immunotherapy with targeted regulation of iron and iron-dependent regulated cell death (ferroptosis) may be a focus of future research.
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Affiliation(s)
- Lesang Shen
- Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310009, China
| | - Yunxiang Zhou
- Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Haifei He
- Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Wuzhen Chen
- Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310009, China
| | - Cameron Lenahan
- Burrell College of Osteopathic Medicine, Las Cruces, NM, USA
| | - Xiaoyi Li
- Department of Nuclear Medicine and PET-CT Center, The Second Affiliated Hospital, Zhejiang University, Hangzhou 310009, China
| | - Yongchuan Deng
- Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Anwen Shao
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Jian Huang
- Department of Breast Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310009, China
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Samara A, Shapira S, Lubin I, Shpilberg O, Avigad S, Granot G, Raanani P. Deferasirox induces cyclin D1 degradation and apoptosis in mantle cell lymphoma in a reactive oxygen species- and GSK3β-dependent mechanism. Br J Haematol 2021; 192:747-760. [PMID: 33521925 DOI: 10.1111/bjh.17284] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/12/2020] [Accepted: 11/24/2020] [Indexed: 01/29/2023]
Abstract
Mantle cell lymphoma (MCL) is a difficult-to-treat B-cell malignancy characterized by cyclin D1 (CD1) overexpression. Targeting CD1 in MCL has been shown to be of therapeutic significance. However, treatment of MCL remains challenging since patients are still subject to early and frequent relapse of the disease. To ensure their high proliferation rate, tumour cells have increased iron needs, making them more susceptible to iron deprivation. Indeed, several iron chelators proved to be effective anti-cancer agents. In this study, we demonstrate that the clinically approved iron chelator deferasirox (DFX) exerts an anti-tumoural effect in MCL cell lines and patient cells. The exposure of MCL cells to clinically feasible concentrations of DFX resulted in growth inhibition, cell cycle arrest and induction of apoptosis. We show that DFX unfolds its cytotoxic effect by a rapid induction of reactive oxygen species (ROS) that leads to oxidative stress and severe DNA damage and by triggering CD1 proteolysis in a mechanism that requires its phosphorylation on T286 by glycogen synthase kinase-3β (GSK3β). Moreover, we demonstrate that DFX mediates CD1 proteolysis by repressing the phosphatidylinositol 3-kinase (PI3K)/AKT/GSK3β pathway via ROS generation. Our data suggest DFX as a potential therapeutic option for MCL and paves the way for more treatment options for these patients.
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Affiliation(s)
- Aladin Samara
- Felsenstein Medical Research Center, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel
| | - Saar Shapira
- Felsenstein Medical Research Center, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel
| | - Ido Lubin
- Felsenstein Medical Research Center, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel
| | - Ofer Shpilberg
- Institute of Hematology, Assuta Medical Center, and School of Medicine, Ariel University, Ariel, Israel
| | - Smadar Avigad
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Galit Granot
- Felsenstein Medical Research Center, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel
| | - Pia Raanani
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.,Institute of Hematology, Davidoff Cancer Center, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel
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Abstract
Cancer cells accumulate iron to supplement their aberrant growth and metabolism. Depleting cells of iron by iron chelators has been shown to be selectively cytotoxic to cancer cells in vitro and in vivo. Iron chelators are effective at combating a range of cancers including those which are difficult to treat such as androgen insensitive prostate cancer and cancer stem cells. This review will evaluate the impact of iron chelation on cancer cell survival and the underlying mechanisms of action. A plethora of studies have shown iron chelators can reverse some of the major hallmarks and enabling characteristics of cancer. Iron chelators inhibit signalling pathways that drive proliferation, migration and metastasis as well as return tumour suppressive signalling. In addition to this, iron chelators stimulate apoptotic and ER stress signalling pathways inducing cell death even in cells lacking a functional p53 gene. Iron chelators can sensitise cancer cells to PARP inhibitors through mimicking BRCAness; a feature of cancers trademark genomic instability. Iron chelators target cancer cell metabolism, attenuating oxidative phosphorylation and glycolysis. Moreover, iron chelators may reverse the major characteristics of oncogenic transformation. Iron chelation therefore represent a promising selective mode of cancer therapy.
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46
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Votavova H, Urbanova Z, Kundrat D, Dostalova Merkerova M, Vostry M, Hruba M, Cermak J, Belickova M. Modulation of the Immune Response by Deferasirox in Myelodysplastic Syndrome Patients. Pharmaceuticals (Basel) 2021; 14:ph14010041. [PMID: 33430232 PMCID: PMC7825690 DOI: 10.3390/ph14010041] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/03/2021] [Accepted: 01/05/2021] [Indexed: 01/02/2023] Open
Abstract
Deferasirox (DFX) is an oral iron chelator used to reduce iron overload (IO) caused by frequent blood cell transfusions in anemic myelodysplastic syndrome (MDS) patients. To study the molecular mechanisms by which DFX improves outcome in MDS, we analyzed the global gene expression in untreated MDS patients and those who were given DFX treatment. The gene expression profiles of bone marrow CD34+ cells were assessed by whole-genome microarrays. Initially, differentially expressed genes (DEGs) were determined between patients with normal ferritin levels and those with IO to address the effect of excessive iron on cellular pathways. These DEGs were annotated to Gene Ontology terms associated with cell cycle, apoptosis, adaptive immune response and protein folding and were enriched in cancer-related pathways. The deregulation of multiple cancer pathways in iron-overloaded patients suggests that IO is a cofactor favoring the progression of MDS. The DEGs between patients with IO and those treated with DFX were involved predominantly in biological processes related to the immune response and inflammation. These data indicate DFX modulates the immune response mainly via neutrophil-related genes. Suppression of negative regulators of blood cell differentiation essential for cell maturation and upregulation of heme metabolism observed in DFX-treated patients may contribute to the hematopoietic improvement.
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Affiliation(s)
- Hana Votavova
- Department of Genomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20 Prague, Czech Republic; (H.V.); (D.K.); (M.D.M.); (M.V.); (M.H.)
| | - Zuzana Urbanova
- First Faculty of Medicine, Charles University, Katerinská 32, 121 08 Prague, Czech Republic;
- Department of Clinical Hematology, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20 Prague, Czech Republic;
| | - David Kundrat
- Department of Genomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20 Prague, Czech Republic; (H.V.); (D.K.); (M.D.M.); (M.V.); (M.H.)
| | - Michaela Dostalova Merkerova
- Department of Genomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20 Prague, Czech Republic; (H.V.); (D.K.); (M.D.M.); (M.V.); (M.H.)
| | - Martin Vostry
- Department of Genomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20 Prague, Czech Republic; (H.V.); (D.K.); (M.D.M.); (M.V.); (M.H.)
| | - Monika Hruba
- Department of Genomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20 Prague, Czech Republic; (H.V.); (D.K.); (M.D.M.); (M.V.); (M.H.)
- First Faculty of Medicine, Charles University, Katerinská 32, 121 08 Prague, Czech Republic;
| | - Jaroslav Cermak
- Department of Clinical Hematology, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20 Prague, Czech Republic;
| | - Monika Belickova
- Department of Genomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, 128 20 Prague, Czech Republic; (H.V.); (D.K.); (M.D.M.); (M.V.); (M.H.)
- Correspondence: ; Tel.: +420-221-977-305
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Relation of Metal-Binding Property and Selective Toxicity of 8-Hydroxyquinoline Derived Mannich Bases Targeting Multidrug Resistant Cancer Cells. Cancers (Basel) 2021; 13:cancers13010154. [PMID: 33466433 PMCID: PMC7796460 DOI: 10.3390/cancers13010154] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/25/2020] [Accepted: 12/24/2020] [Indexed: 12/18/2022] Open
Abstract
Simple Summary Effective treatment of cancer is often limited by the resistance of cancer cells to chemotherapy. A well-described mechanism supporting multidrug resistance (MDR) relies on the efflux of toxic drugs from cancer cells, mediated by P-glycoprotein (Pgp). Circumventing Pgp-mediated resistance is expected to make a significant contribution to improved therapy of malignancies. Interestingly, MDR cells exhibit paradoxical hypersensitivity towards a diverse set of anticancer chelators. In this study we explore the relation of chemical and structural properties influencing metal binding and toxicity of a set of 8-hydroxyquinoline derivatives to reveal key characteristics governing “MDR-selective” activity. We find that subtle changes in the stability and redox activity of the biologically relevant metal complexes significantly influence MDR-selective toxicity. Our results underline the importance of chelation in MDR-selective toxicity, suggesting that the collateral sensitivity of MDR cells may be targeted by preferential iron deprivation or the formation of redox-active copper(II) complexes. Abstract Resistance to chemotherapeutic agents is a major obstacle in cancer treatment. A recently proposed strategy is to target the collateral sensitivity of multidrug resistant (MDR) cancer. Paradoxically, the toxicity of certain metal chelating agents is increased, rather than decreased, by the function of P-glycoprotein (Pgp), which is known to confer resistance by effluxing chemotherapeutic compounds from cancer cells. We have recently characterized and compared the solution’s chemical properties including ligand protonation and the metal binding properties of a set of structurally related 8-hydroxyquinoline derived Mannich bases. Here we characterize the impact of the solution stability and redox activity of their iron(III) and copper(II) complexes on MDR-selective toxicity. Our results show that the MDR-selective anticancer activity of the studied 8-hydroxyquinoline derived Mannich bases is associated with the iron deprivation of MDR cells and the preferential formation of redox-active copper(II) complexes, which undergo intracellular redox-cycling to induce oxidative stress.
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Rodríguez-García A, García-Vicente R, Morales ML, Ortiz-Ruiz A, Martínez-López J, Linares M. Protein Carbonylation and Lipid Peroxidation in Hematological Malignancies. Antioxidants (Basel) 2020; 9:E1212. [PMID: 33271863 PMCID: PMC7761105 DOI: 10.3390/antiox9121212] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/20/2020] [Accepted: 11/28/2020] [Indexed: 02/07/2023] Open
Abstract
Among the different mechanisms involved in oxidative stress, protein carbonylation and lipid peroxidation are both important modifications associated with the pathogenesis of several diseases, including cancer. Hematopoietic cells are particularly vulnerable to oxidative damage, as the excessive production of reactive oxygen species and associated lipid peroxidation suppress self-renewal and induce DNA damage and genomic instability, which can trigger malignancy. A richer understanding of the clinical effects of oxidative stress might improve the prognosis of these diseases and inform therapeutic strategies. The most common protein carbonylation and lipid peroxidation compounds, including hydroxynonenal, malondialdehyde, and advanced oxidation protein products, have been investigated for their potential effect on hematopoietic cells in several studies. In this review, we focus on the most important protein carbonylation and lipid peroxidation biomarkers in hematological malignancies, their role in disease development, and potential treatment implications.
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Affiliation(s)
- Alba Rodríguez-García
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (i+12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, ES 28041 Madrid, Spain; (A.R.-G.); (R.G.-V.); (M.L.M.); (A.O.-R.); (J.M.-L.)
| | - Roberto García-Vicente
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (i+12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, ES 28041 Madrid, Spain; (A.R.-G.); (R.G.-V.); (M.L.M.); (A.O.-R.); (J.M.-L.)
| | - María Luz Morales
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (i+12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, ES 28041 Madrid, Spain; (A.R.-G.); (R.G.-V.); (M.L.M.); (A.O.-R.); (J.M.-L.)
| | - Alejandra Ortiz-Ruiz
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (i+12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, ES 28041 Madrid, Spain; (A.R.-G.); (R.G.-V.); (M.L.M.); (A.O.-R.); (J.M.-L.)
| | - Joaquín Martínez-López
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (i+12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, ES 28041 Madrid, Spain; (A.R.-G.); (R.G.-V.); (M.L.M.); (A.O.-R.); (J.M.-L.)
- Department of Medicine, Medicine School, Universidad Complutense de Madrid, ES 28040 Madrid, Spain
| | - María Linares
- Department of Translational Hematology, Instituto de Investigación Hospital 12 de Octubre (i+12), Hematological Malignancies Clinical Research Unit H120-CNIO, CIBERONC, ES 28041 Madrid, Spain; (A.R.-G.); (R.G.-V.); (M.L.M.); (A.O.-R.); (J.M.-L.)
- Department of Biochemistry and Molecular Biology, Pharmacy School, Universidad Complutense de Madrid, ES 28040 Madrid, Spain
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Iron Dysregulation in Human Cancer: Altered Metabolism, Biomarkers for Diagnosis, Prognosis, Monitoring and Rationale for Therapy. Cancers (Basel) 2020; 12:cancers12123524. [PMID: 33255972 PMCID: PMC7761132 DOI: 10.3390/cancers12123524] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/21/2020] [Accepted: 11/24/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Iron is the more abundant metal ion in humans. It is essential for life as it has a role in various cellular processes involved, for instance, in cell metabolism and DNA synthesis. These functions are crucial for cell proliferation, and it is therefore not surprising that iron is accumulated in tumors. In this review, we describe normal and altered iron homeostasis mechanisms. We also provide a vision of iron-related proteins with altered expression in cancers and discuss their potential as diagnostic and/or prognostic biomarkers. Finally, we give an overview of therapeutic strategies acting on iron metabolism to fight against cancers. Abstract Iron (Fe) is a trace element that plays essential roles in various biological processes such as DNA synthesis and repair, as well as cellular energy production and oxygen transport, and it is currently widely recognized that iron homeostasis is dysregulated in many cancers. Indeed, several iron homeostasis proteins may be responsible for malignant tumor initiation, proliferation, and for the metastatic spread of tumors. A large number of studies demonstrated the potential clinical value of utilizing these deregulated proteins as prognostic and/or predictive biomarkers of malignancy and/or response to anticancer treatments. Additionally, the iron present in cancer cells and the importance of iron in ferroptosis cell death signaling pathways prompted the development of therapeutic strategies against advanced stage or resistant cancers. In this review, we select relevant and promising studies in the field of iron metabolism in cancer research and clinical oncology. Besides this, we discuss some co-existing discrepant findings. We also present and discuss the latest lines of research related to targeting iron, or its regulatory pathways, as potential promising anticancer strategies for human therapy. Iron chelators, such as deferoxamine or iron-oxide-based nanoparticles, which are already tested in clinical trials, alone or in combination with chemotherapy, are also reported.
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50
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Jiang G, Su Z, Liang X, Huang Y, Lan Z, Jiang X. Long non-coding RNAs in prostate tumorigenesis and therapy (Review). Mol Clin Oncol 2020; 13:76. [PMID: 33005410 DOI: 10.3892/mco.2020.2146] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Accepted: 06/18/2020] [Indexed: 12/19/2022] Open
Abstract
Prostate cancer (PCa) is one of the most frequently diagnosed malignancy. Although there have been many advances in PCa diagnosis and therapy, the concrete mechanism remains unknown. Long non-coding RNAs (lncRNAs) are novel biomarkers associated with PCa, and their dysregulated expression is closely associated with risk stratification, diagnosis and carcinogenesis. Accumulating evidence has suggested that lncRNAs play important roles in prostate tumorigenesis through relevant pathways, such as androgen receptor interaction and PI3K/Akt. The present review systematically summarized the potential clinical utility of lncRNAs and provided a novel guide for their function in PCa.
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Affiliation(s)
- Ganggang Jiang
- Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, P.R. China.,Department of Center Laboratory, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, P.R. China
| | - Zhengming Su
- Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, P.R. China.,Department of Center Laboratory, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, P.R. China
| | - Xue Liang
- Department of Center Laboratory, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, P.R. China
| | - Yiqiao Huang
- Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, P.R. China
| | - Ziquan Lan
- Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, P.R. China
| | - Xianhan Jiang
- Department of Urology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, P.R. China.,Department of Center Laboratory, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, P.R. China
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