{"title":"Iron and Its Role in Cancer Defense: A Double-Edged Sword.","authors":"Frank Thévenod","doi":"10.1515/9783110470734-021","DOIUrl":"https://doi.org/10.1515/9783110470734-021","url":null,"abstract":"<p><p>Iron (Fe) is an essential metal, vital for biological functions, including electron transport, DNA synthesis, detoxification, and erythropoiesis that all contribute to metabolism, cell growth, and proliferation. Interactions between Fe and O2 can result in the generation of reactive oxygen species (ROS), which is based on the ability of Fe to redox cycle. Excess Fe may cause oxidative damage with ensuing cell death, but DNA damage may also lead to permanent mutations. Hence Fe is carcinogenic and may initiate tumor formation and growth, and also nurture the tumor microenvironment and metastasis. However, Fe can also contribute to cancer defense. Fe may induce toxic ROS and/or initiate specific forms of cell death, including ferroptosis that will benefit cancer treatment. Furthermore, Fe-binding and Fe-regulatory proteins, such as hepcidin, lipocalin-2/NGAL, heme oxygenase-1, ferritin, and iron-sulfur clusters can display antitumor properties under specific conditions and in particular cancer types. In addition, the milk protein lactoferrin may synergize with other established anticancer agents in the prevention and therapy of cancer. Consequently, drugs that target Fe metabolism in tumors are promising candidates for the prevention and therapy of cancer, but consideration of context specificity (e.g., tumor type; systemic versus tumor microenvironment Fe homeostasis) is mandatory.</p>","PeriodicalId":18698,"journal":{"name":"Metal ions in life sciences","volume":"18 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/9783110470734-021","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35787884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Deceptively Similar Ruthenium(III) Drug Candidates KP1019 and NAMI-A Have Different Actions. What Did We Learn in the Past 30 Years?","authors":"Enzo Alessio, Luigi Messori","doi":"10.1515/9783110470734-011","DOIUrl":"https://doi.org/10.1515/9783110470734-011","url":null,"abstract":"<p><p>The general interest in anticancer metal-based drugs and some encouraging pharmacological results obtained at the beginning of the investigations on innovative Ru-based drugs triggered a lot of attention on NAMI-A and KP1019, the two Ru(III) coordination compounds that are the subject of this review. This great attention led to a considerable amount of scientific results and, more importantly, to their eventual admission into clinical trials. Both complexes share a relatively low systemic toxicity that allows reaching rather high dosages, comparable to those of carboplatin. Soon it became evident that NAMI-A and KP1019, in spite of their structural similarity, manifest very distinct chemical and biological properties. The pharmacological performances qualified KP1019 mainly as a cytotoxic drug for the treatment of platinum-resistant colorectal cancers, whereas NAMI-A gained the reputation of a potential anticancer drug with negligible effects on the primary tumor but a pronounced ability to affect metastases. We believe that a strictly comparative exam of NAMI-A and KP1019, based on the substantial body of studies accomplished since their discovery almost 30 years ago, might be an useful exercise, both for assessing the state of the art in terms of biological and clinical profiles, and of the inherent mechanisms, and for envisaging possible future developments in the light of past achievements.</p>","PeriodicalId":18698,"journal":{"name":"Metal ions in life sciences","volume":"18 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/9783110470734-011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35789023","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Coordination Complexes of Titanium(IV) for Anticancer Therapy.","authors":"Edit Y Tshuva, Maya Miller","doi":"10.1515/9783110470734-014","DOIUrl":"https://doi.org/10.1515/9783110470734-014","url":null,"abstract":"<p><p>Titanium(IV) coordination complexes represent attractive alternatives to platinumbased anticancer drugs. The advantage of the titanium metal lies in its low toxicity, and the hydrolysis of titanium(IV) coordination complexes in biological water-based environment to the safe and inert titanium dioxide is an enormous benefit. On the other hand, the rapid hydrolysis of titanium(IV) complexes in biological environment and their rich aquatic chemistry hampered the exploration and the development of effective compounds. Titanium(IV) complexes were the first to enter clinical trials for cancer treatment following the success of platinum-based chemotherapy, with the pioneering compounds titanocene dichloride and budotitane. Despite the high efficacy and low toxicity observed in vivo, the compounds failed the trials due to insufficient efficacy to toxicity ratio and formulation complications. The rapid hydrolysis of the complexes led to formation of multiple undefined aggregates and difficulties in isolating and identifying the particular active species and its precise cellular target. Numerous derivatives with different labile ligands or substitutions on the inert ones contributed to improve the complex anticancer features, and the best ones were comparable with, and occasionally better than cisplatin. Hydrolytic stability was improved in some cases but remained challenging. The following generation of phenolato-based complexes that came three decades later exhibited high activity and markedly improved stability, where no dissociation was observed for weeks in biological solutions. Complexes of no labile ligands whatsoever that remain intact in solution demonstrated in vitro and in vivo efficacy, with no signs of toxicity to the treated animals. Mechanistic insights gained for the different complexes analyzed include, among others, possible interaction with DNA and induction of apoptosis. Such complexes are highly promising for future exploration and clinical development.</p>","PeriodicalId":18698,"journal":{"name":"Metal ions in life sciences","volume":"18 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/9783110470734-014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35789026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Nucleic Acid Quadruplexes and Metallo-Drugs.","authors":"Ramon Vilar","doi":"10.1515/9783110470734-018","DOIUrl":"https://doi.org/10.1515/9783110470734-018","url":null,"abstract":"<p><p>Guanine-rich sequences of DNA can readily fold into tetra-stranded helical assemblies known as G-quadruplexes (G4s). It has been proposed that these structures play important biological roles in transcription, translation, replication, and telomere maintenance. Therefore, over the past 20 years they have been investigated as potential drug targets for small molecules including metal complexes. This chapter provides an overview of the different classes of metal complexes as G4-binders and discusses the application of these species as optical probes for G-quadruplexes as well as metallo-drugs.</p>","PeriodicalId":18698,"journal":{"name":"Metal ions in life sciences","volume":"18 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/9783110470734-018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35789030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nicholas P Farrell, Anil K Gorle, Erica J Peterson, Susan J Berners-Price
{"title":"Metalloglycomics.","authors":"Nicholas P Farrell, Anil K Gorle, Erica J Peterson, Susan J Berners-Price","doi":"10.1515/9783110470734-010","DOIUrl":"https://doi.org/10.1515/9783110470734-010","url":null,"abstract":"<p><p>Glycosaminoglycans (GAGs) such as heparin and heparan sulfate (HS) are large complex carbohydrate molecules that bind to a wide variety of proteins and exercise important physiological and pathological processes. This chapter focuses on the concept of metalloglycomics and reviews the structure and conformation of GAGs and the role of various metal ions during the interaction of GAGs with their biological partners such as proteins and enzymes. The use of metal complexes in heparin analysis is discussed. Cleavage of heparan sulfate proteoglycans (HSPGs) by the enzyme heparanase modulates tumor-related events including angiogenesis, cell invasion, metastasis, and inflammation. HS is identified as a ligand receptor for polynuclear platinum complexes (PPCs) defining a new mechanism of cellular accumulation for platinum drugs with implications for tumor selectivity. The covalent and noncovalent interaction of PPCs with GAGs and the functional consequences of strong binding with HS are explained in detail. Sulfate cluster anchoring shields the sulfates from recognition by charged protein residues preventing the exercise of the HS-enzyme/protein function, such as growth factor recognition and the activity of heparanase on HS. The cellular consequences are inhibition of invasion and angiogenesis. Metalloglycomics is a potentially rich new area of endeavor for bioinorganic chemists to study the relevance of intrinsic metal ions in heparin/ HS-protein interactions and for development of new compounds for therapeutic, analytical, and imaging applications.</p>","PeriodicalId":18698,"journal":{"name":"Metal ions in life sciences","volume":"18 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/9783110470734-010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35789104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Targeting Zinc(II) Signalling to Prevent Cancer.","authors":"Silvia Ziliotto, Olivia Ogle, Kathryn M Taylor","doi":"10.1515/9783110470734-023","DOIUrl":"https://doi.org/10.1515/9783110470734-023","url":null,"abstract":"<p><p>Zinc is an important element that is gaining momentum as a potential target for cancer therapy. In recent years zinc has been accepted as a second messenger that is now recognized to be able to activate many signalling pathways within a few minutes of an extracellular stimulus by release of zinc(II) from intracellular stores. One of the major effects of this store release of zinc is to inhibit a multitude of tyrosine phosphatases which will prevent the inactivation of tyrosine kinases and hence, encourage further activation of tyrosine kinasedependent signalling pathways. Most of these signalling pathways are not only known to be involved in driving aberrant cancer growth, they are usually the main driving force. All this data together now positions zinc and zinc signalling as potentially important new targets to prevent aggressive cancer growth.</p>","PeriodicalId":18698,"journal":{"name":"Metal ions in life sciences","volume":"18 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/9783110470734-023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35787886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Medicinal Chemistry of Gold Anticancer Metallodrugs.","authors":"Angela Casini, Raymond Wai-Yin Sun, Ingo Ott","doi":"10.1515/9783110470734-013","DOIUrl":"https://doi.org/10.1515/9783110470734-013","url":null,"abstract":"<p><p>Since ancient times gold and its complexes have been used as therapeutics against different diseases. In modern medicine gold drugs have been applied for the treatment of rheumatoid arthritis, however, recently other medical applications have come into the focus of inorganic medicinal chemistry. This chapter provides a non-comprehensive overview of key developments in the field of gold anticancer drugs. Exciting findings on gold(I) and gold(III) complexes as antitumor agents are summarized together with a discussion of relevant aspects of their modes of action.</p>","PeriodicalId":18698,"journal":{"name":"Metal ions in life sciences","volume":"18 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/9783110470734-013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35789025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Viktor Brabec, Jana Kasparkova, Vijay Menon, Nicholas P Farrell
{"title":"Polynuclear Platinum Complexes. Structural Diversity and DNA Binding.","authors":"Viktor Brabec, Jana Kasparkova, Vijay Menon, Nicholas P Farrell","doi":"10.1515/9783110470734-008","DOIUrl":"https://doi.org/10.1515/9783110470734-008","url":null,"abstract":"<p><p>Polynuclear platinum complexes (PPCs) represent a discrete structural class of DNA-binding agents with excellent antitumor properties. The use of at least two platinum coordinating units automatically means that multifunctional DNA binding modes are possible. The structural variability inherent in a polynuclear platinum structure can be harnessed to produce discrete modes of DNA binding, with conformational changes distinct from and indeed inaccessible to, the mononuclear agents such as cisplatin. Since our original contributions in this field a wide variety of dinuclear complexes especially have been prepared, their DNA binding studied, and potential relevance to cytotoxicity examined. This chapter focuses on how DNA structure and reactivity is modulated through interactions with PPCs with emphasis on novel aspects of such structure and reactivity. How these major changes are further reflected in damaged DNA-protein binding and cellular effects are reviewed. We further review, for the first time, the great structural diversity achieved in PPC complex design and summarize their major DNA binding effects.</p>","PeriodicalId":18698,"journal":{"name":"Metal ions in life sciences","volume":"18 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/9783110470734-008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35789101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Gallium Complexes as Anticancer Drugs.","authors":"Christopher R Chitambar","doi":"10.1515/9783110470734-016","DOIUrl":"https://doi.org/10.1515/9783110470734-016","url":null,"abstract":"<p><p>Clinical trials have shown gallium nitrate, a group 13 (formerly IIIa) metal salt, to have antineoplastic activity against non-Hodgkin's lymphoma and urothelial cancers. Interest in gallium as a metal with anticancer properties emerged when it was discovered that 67Ga(III) citrate injected in tumor-bearing animals localized to sites of tumor. Animal studies showed non-radioactive gallium nitrate to inhibit the growth of implanted solid tumors. Following further evaluation of its efficacy and toxicity in animals, gallium nitrate, Ga(NO3)3, was designated an investigational drug by the National Cancer Institute (USA) and advanced to Phase 1 and 2 clinical trials. Gallium(III) shares certain chemical characteristics with iron(III) which enable it to interact with iron-binding proteins and disrupt iron-dependent tumor cell growth. Gallium's mechanisms of action include the inhibition of cellular iron uptake and disruption of intracellular iron homeostasis, these effects result in inhibition of ribonucleotide reductase and mitochondrial function, and changes in the expression in proteins of iron transport and storage. Whereas the growth-inhibitory effects of gallium become apparent after 24 to 48 hours of incubation of cells, an increase in intracellular reactive oxygen species (ROS) is seen with 1 to 4 hours of incubation. Gallium-induced ROS consequently triggers the upregulation of metallothionein and hemoxygenase-1 genes. Beyond the first generation of gallium salts such as gallium nitrate and gallium chloride, a new generation of gallium-ligand complexes such as tris(8-quinolinolato)gallium(III) (KP46) and gallium maltolate has emerged. These agents are being evaluated in the clinic while other ligands for gallium are in preclinical development. These newer agents appear to possess greater antitumor efficacy and a broader spectrum of antineoplastic activity than the earlier generation of gallium compounds.</p>","PeriodicalId":18698,"journal":{"name":"Metal ions in life sciences","volume":"18 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/9783110470734-016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35789028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Platinum(IV) Prodrugs.","authors":"V Venkatesh, Peter J Sadler","doi":"10.1515/9783110470734-009","DOIUrl":"https://doi.org/10.1515/9783110470734-009","url":null,"abstract":"<p><p>This chapter is an overview of recent progress in the design of Pt(IV) prodrugs. These kinetically-inert octahedral prodrugs can be reduced in cancer cells to active squareplanar Pt(II) complexes, for example by intracellular reducing agents such as glutathione or by photoexcitation. The additional axial ligands in Pt(IV) complexes which are released on reduction, allow bioactive molecules to be delivered which can act synergistically with Pt(II) in killing cancer cells, or act as targeting vectors, allow attachment to polymer and nanoparticle delivery systems, or labelling with fluorescent probes. Pt(IV) prodrugs have yet to be approved for clinical use, although some offer the promise of increased efficacy and reduced side effects.</p>","PeriodicalId":18698,"journal":{"name":"Metal ions in life sciences","volume":"18 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1515/9783110470734-009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35789100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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