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Role of copper in tumour angiogenesis - Clinical implications
Abstract
The formation of new blood vessels is the initial step in progressive tumour development and metastasis. The first stage in tumour angiogenesis is the activation of endothelial cells. Copper ions stimulate proliferation and migration of endothelial cells. It has been shown that serum copper concentration increases as the cancer disease progresses and correlates with tumour incidence and burden. Copper ions also activate several proangiogenic factors, e.g., vascular endothelial growth factor, basic fibroblast growth factor, tumour necrosis factor alpha and interleukin 1. This review concerns a brief introduction into the basics of tumour blood vessel development as well as the regulatory mechanisms of this process. The role of copper ions in tumour angiogenesis is discussed. The new antiangiogenic therapies based on a reduction of copper levels in tumour microenvironment are reviewed.
... Elevated copper levels is a well-documented metabolic difference between malignant cells and 'normal' cells [35,36]. Rizvi A et al. have demonstrated that calcitriol, the metabolically active form of vitamin D, interacted with copper and produced reactive oxygen species by Fenton-Haber-Weiss like reactions which caused irreparable DNA damage in carcinoma cells and induced the consequent selective cell death of malignant cells but spare normal cells. ...
... Whether JP3 affects enzymatic and non-enzymatic scavengers of reactive oxygen species in cancer cells or not needs more experiments. Elevated copper levels are a well-documented metabolic difference between malignant cells and 'normal' cells [35,36]. Rizvi A et al. have demonstrated that calcitriol, the metabolically active form of vitamin D, interacted with copper and produced reactive oxygen species by Fenton-Haber-Weiss like reactions which caused irreparable DNA damage in carcinoma cells and induced the consequent selective cell death of malignant cells but spare normal cells. ...
Background: Cisplatin (DDP) is a highly effective chemotherapeutic agent to most solid tumors including gastric cancer (GC), however, its clinical value is limited due to severe toxic side effects and secondary drug resistance. JP3, a JWA protein based MMP2-targeted polypeptide, known to inhibit the growth of GC in vivo. However, the bidirectional effects of JP3 in DDP-resistant GC and normal cells have not been demonstrated. The present study aims to investigate the actions of JP3 on protecting normal cells from the toxicity of DDP while enhancing its anti-tumor effects on GC cells.
Methods: Routine laboratory experimental methods including CCK-8 assay, Western blotting, Hoechst staining, immunofluorescence (IF) and qRT-PCR were used in mechanism investigation; protein docking analysis and coimmunoprecipitation (Co-IP) were used for prediction and confirmation of interactions between JP3 and CK2. Mouse xenograft model was used for screening the treatment of JP3 plus DDP on GC growth.
Results: DDP showed similar toxicities to normal cells and DDP-resistant GC cells; JP3 competitively inhibited the binding of XRCC1 to CK2, reduced the DNA repair and anti-apoptosis capacity of DDP-resistant GC cells in combination with DDP treatment; meanwhile, JP3 protected normal cells from DDP-induced oxidative stress and DNA damage through ERK/Nrf2 signaling. JP3 combined with DDP showed similar bidirectional effects in vivo.
Conclusions: JP3 enhanced the inhibitory effects of DDP on tumor growth while reduced toxic side effects of DDP on normal cells. The results of this study provide a new insight for the treatment of drug-resistant GC.
... The term tumor microenvironment (TME) originated from the proposed ecological terminology (178), which is used to describe the internal and external environment of tumors or tumor cells with the ability of self-renewal and tumor driving (144). ...
As a biologically essential transition metal, copper is widely involved in various enzymatic reactions and crucial biological processes in the body. It plays an increasingly important role in maintaining normal cellular metabolism and supporting the growth and development of the human body. As a trace element, copper maintains the dynamic balance of its concentration in body fluids through active homeostatic mechanisms. Both excess and deficiency of copper ions can impair cell function, ultimately leading to cell damage and death. Cuproptosis is a novel form of cell death where copper ions cause cell death by directly binding to the lipoylated components of the citric acid cycle (CAC) in mitochondrial respiration and interfering with the levels of iron-sulfur cluster (Fe-S cluster) proteins, ultimately causing protein toxic stress. Its primary characteristics are Cu2+ concentration dependence and high expression in mitochondrial respiratory cells. Recent research has revealed that, compared to other forms of programmed cell death such as apoptosis, necrosis, and autophagy, cuproptosis has unique morphological and biochemical features. Cuproptosis is associated with the occurrence and development of various diseases, including cancer, neurodegenerative diseases, and cardiovascular diseases. This article focuses on a review of the relevance of cuproptosis in gastric cancer (GC).
... Copper ion is closely associated with promoting angiogen esis [ 76 ]. Gérard et al. [ 77 ] reported that copper ion promotes endothelial cell proliferation and enhances angiogenesis in vitro and in vivo. ...
The recent discovery of cuproptosis, a novel copper-ion-induced cell death pathway, has suggested the novel therapeutic potential for treating heterogeneous and drug-resistant cancers. Currently, copper ionophore-based therapeutics have been designed to treat cancers, utilizing copper ions as a strategic tool to impede tumor proliferation and promote cellular demise. However, limitations of copper ionophore-based therapies include nontargeted delivery of copper ions, low tumor accumulation, and short half-life. Strategies to enhance specificity involve targeting intracellular cuproptosis mechanisms using nanotechnology-based drugs. Additionally, the importance of exploring combination therapies cannot be overstated, as they are a key strategy in improving the efficacy of cancer treatments. Recent studies have reported the anticancer effects of nanomedicines that can induce cuproptosis of cancer both in vitro and in vivo. These cuproptosis-targeted nanomedicines could improve delivery efficiency with the pharmacokinetic properties of copper ion, resulting in increasing cuproptosis-based anticancer effects. This review will summarize the intricate nexus between copper ion and carcinogenesis, examining the pivotal roles of copper homeostasis and its dysregulation in cancer progression and fatality. Furthermore, we will introduce the latest advances in cuproptosis-targeted nanomedicines for cancer treatment. Finally, the challenges in cuproptosis-based nanomedicines will be discussed for future development directions.
... In various cancer types, including EC, heightened copper concentrations have been documented [27]. The oxidative stress engendered by copper may induce angiogenesis in EC, leading to the proliferation of new vasculature from a previously dormant state, thus fueling tumor progression [28]. Excess copper ions can also interact with lipid-acylated components within the tricarboxylic acid (TCA) cycle, culminating in protein aggregation and the disintegration of iron-sulfur cluster proteins, which initiate proteotoxic stress and cell death [29]. ...
Background
Endometrial cancer (EC) stands as the predominant gynecological malignancy impacting the female reproductive system on a global scale. N6‐methyladenosine, cuproptosis‐ and ferroptosis‐related biomarker is beneficial to the prognostic of tumor patients. Nevertheless, the correlation between m6A‐modified lncRNAs and ferroptosis, copper‐induced apoptosis in the initiation and progression of EC remains unexplored in existing literature.
Aims
In this study, based on bioinformatics approach, we identified lncRNAs co‐expressing with cuproptosis‐, ferroptosis‐, m6A‐ related lncRNAs from expression data of EC. By constructing the prognosis model in EC, we screened hub lncRNA signatures affecting prognosis of EC patients. Furthermore, the guiding value of m6A‐modified ferroptosis‐related lncRNA (mfrlncRNA) features was assessed in terms of prognosis, immune microenvironment, and drug sensitivity.
Method
Our research harnessed gene expression data coupled with clinical insights derived from The Cancer Genome Atlas (TCGA) collection. To forge prognostic models, we adopted five machine learning approaches, assessing their efficacy through C‐index and time‐independent ROC analysis. We pinpointed prognostic indicators using the LASSO Cox regression approach. Moreover, we delved into the biological and immunological implications of the discovered lncRNA prognostic signatures.
Results
The survival rate for the low‐risk group was markedly higher than that for the high‐risk group, as evidenced by a significant log‐rank test (p < 0.001). The LASSO Cox regression model yielded concordance indices of 0.76 for the training set and 0.77 for the validation set, indicating reliable prognostic accuracy. Enrichment analysis of gene functions linked the identified signature predominantly to endopeptidase inhibitor activity, highlighting the signature's potential implications. Additionally, immune function and drug density emphasized the importance of early diagnosis in EC.
Conclusion
Five hub lncRNAs in EC were identified through constructing the prognosis model. Those genes might be potential biomarkers to provide valuable reference for targeted therapy and prognostic assessment of EC.
... However, copper is also known to induce the proliferation of cancer cells, as it stimulates the proliferation and migration of endothelial cells, as well as numerous pro-angiogenic reactions [13], which are the first stages of tumor angiogenesis [14]. It has been shown, in particular, that serum copper concentration increases as the cancer disease progresses [15]. In view of these contradictory results [16,17], there is a need to find the most suitable copper chelators [18] with the aim of reaching copper homeostasis [19,20]. ...
Since the discovery of cisplatin in the 1960s, the search for metallo-drugs that are more efficient than platinum complexes with negligible side effects has attracted much interest. Among the other metals that have been examined for potential applications as anticancer agents is copper. The interest in copper was recently boosted by the discovery of cuproptosis, a recently evidenced form of cell death mediated by copper. However, copper is also known to induce the proliferation of cancer cells. In view of these contradictory results, there is a need to find the most suitable copper chelators, among which Schiff-based derivatives offer a wide range of possibilities. Gathering several metal complexes in a single, larger entity may provide enhanced properties. Among the nanometric objects suitable for such purpose are dendrimers, precisely engineered hyperbranched macromolecules, which are outstanding candidates for improving therapy and diagnosis. In this review article, we present an overview of the use of a particular Schiff base, namely pyridine–imine, linked to the surface of dendrimers, suitable for complexing copper, and the use of such dendrimer complexes in biology, in particular against cancers.
... Together with iron, this element takes part in the formation of red blood cells. It was also proven that the growth and metabolism of cancer cells, due to the elevated angiogenesis, require more copper [87][88][89][90] . As copper is also strictly associated with the progress of inflammation process, including the cytokines production, during inflammation increased levels of the element are observed in serum 87 . ...
Glioblastoma (GBM) is a fast-growing and aggressive brain tumor which invades the nearby brain tissue but generally does not spread to the distant organs. Nonetheless, if untreated, GBM can result in patient death in time even less than few months from the diagnosis. The influence of the tumor progress on organs other than brain is obvious but still not well described. Therefore, we examined the elemental abnormalities appearing in selected body organs (kidney, heart, spleen, lung) in two rat models of GBM. The animals used for the study were subjected to the implantation of human GBM cell lines (U87MG and T98G) characterized by different levels of invasiveness. The elemental analysis of digested organ samples was carried out using the total reflection X-ray fluorescence (TXRF) method, independently, in three European laboratories utilizing various commercially available TXRF spectrometers. The comparison of the data obtained for animals subjected to T98G and U87MG cells implantation showed a number of elemental anomalies in the examined organs. What is more, the abnormalities were found for rats even if neoplastic tumor did not develop in their brains. The most of alterations for both experimental groups were noted in the spleen and lungs, with the direction of the found element changes in these organs being the opposite. The observed disorders of element homeostasis may result from many processes occurring in the animal body as a result of implantation of cancer cells or the development of GBM, including inflammation, anemia of chronic disease or changes in iron metabolism. Tumor induced changes in organ elemental composition detected in cooperating laboratories were usually in a good agreement. In case of elements with higher atomic numbers (Fe, Cu, Zn and Se), 88% of the results were classified as fully compliant. Some discrepancies between the laboratories were found for lighter elements (P, S, K and Ca). However, also in this case, the obtained results fulfilled the requirements of full (the results from three laboratories were in agreement) or partial agreement (the results from two laboratories were in agreement).
... The background metallome of healthy cells is only known for a limited number of elements, and its evolution with the evolution of the pathologies remain largely unknown. Some elements are clearly carcinogenic, notably heavy metals such as cadmium (Cd), chromium (Cr), mercury (Hg), and tin (Sn), whereas some others, typically Cu and S, vary as a response to cancer progression (9,10). Most often, the nature of these changes is not well understood. ...
Background
The role of metals and trace elements in the progression of cancer can be both passive and active. While some metals have clearly emerged as carcinogens, the homeostasis of other trace elements only trails cancer evolution and therefore offers some potential prognostic values. At this stage, modern-standard datasets including a large number of elements are missing. The present analysis established a first metallomic spectrum by relating the blood concentration of metals and trace elements in patients with sarcoma with survival data.
Methods
Patients with sarcoma and controls were retrospectively selected from the International Sarcoma Kindred Study database. Blood samples were prospectively collected at the Leon Bérard Cancer Center from February 2012 to July 2019. Stable specimens and copper isotopes (65Cu/63Cu) were analyzed using Triple Quadrupole ICP-MS and the MC-ICP-MS Nu Plasma HR 500. Wilcoxon rank sum test, log-rank test, and multivariate Cox regression models were used for statistics.
Results
In total, 151 patients and 59 healthy controls were included. At the time of blood sample collection, 62% of patients had locally advanced or metastatic disease, and 49% were undergoing chemotherapy. The median overall survival (OS) was 16.6 months. Copper (Cu), copper/zinc (Cu/Zn) and potassium /rubidium (K/Rb) ratio were significantly higher in patients compared to controls, whereas δ65Cu, selenium (Se), sulfur (S), Rb, K, phosphorus (P), iron (Fe) and Se / S ratio were significantly lower. Cu, Cu / Zn and K / Rb were also significantly higher in advanced compared to early stage disease. Of note, whereas S and Se were significantly correlated in patients, no correlation was observed in controls. Importantly, levels of K, Rb, Se, Fe, P, Si, S, δ65Cu, Cu, S / Se and Cu/Zn ratio were independently associated with OS.
Conclusions
These results depict the metallomic spectrum in sarcoma and highlight substantial variation associated with survival, some of them paving the way for future anti-cancer therapy development
... Among the first transitional metal species, copper is a trace element involved in a series of fundamental biological processes associated with metalloproteins and -enzymes, as well as several related to mitochondrial metabolism [24,25] and acting towards cellular oxidant species protection [26,27]. Even essential metals, metal compounds, or organic compounds at higher doses can present side effects; therefore, copper is essential in healthy cells, and there are homeostatic natural control processes acting to stabilize the level of copper in organisms, but which at higher concentrations can produce tumor growth, angiogenesis, and metastasis [28][29][30][31]. In accordance with these characteristics of copper, it has been considered as a promising component of metallodrugs used in cancer therapy [32], and in the late 1980 s, new mixed chelates-copper (II) complexes were designed and then patented a few years later [33]. ...
In this review, we present a timeline that shows the origin of mixed chelate copper (II) complexes, registered as Mark Title Casiopeínas®, as the first copper (II) compounds proposed as anticancer drugs in 1988 and 1992. In the late twentieth century, the use of essential metals as anticancer agents was not even considered, except for their antifungal or antibacterial effects; also, copper, as gold salts, was used for arthritis problems. The use of essential metals as anticancer drugs to diminish the secondary toxic effects of Cisplatin was our driving force: to find less toxic and even more economical compounds under the rational design of metal chelate complexes. Due to their chemical properties, copper compounds were the choice to continue anticancer drug development. In this order of ideas, the rational designs of mixed chelate–copper (II) complexes (Casiopeínas, (Cas) homoleptic or heteroleptic, depending on the nature of the secondary ligand) were synthesized and fully characterized. In the search for new, more effective, and less toxic drugs, Casiopeína® (Cas) emerged as a family of approximately 100 compounds synthesized from coordinated Cu(II) complexes with proven antineoplastic potential through cytotoxic action. The Cas have the general formula [Cu(N–N)(N–O)]NO3 and [Cu(N–N)(O–O)]NO3, where N–N is an aromatic substituted diimine (1,10-phenanthroline or 2,2′-bipyridine), and the oxygen donor (O–O) is acetylacetonate or salicylaldehyde. Lately, some similar compounds have been developed by other research groups considering a similar hypothesis after Casiopeína’s discoveries had been published, as described herein. As an example of translational medicine criteria, we have covered each step of the established normative process for drug development, and consequently, one of the molecules (Casiopeína III ia (CasIIIia)) has reached the clinical phase I. For these copper compounds, other activities, such as antibacterial, antiparasitic and antiviral, have been discovered.
... When compared to female participants, male subjects had considerably greater copper levels in colon cancer, although this difference was not significant. Other research revealed higher copper levels in certain human neoplasms, such as breast cancer and lymphoma, with many of these studies concentrating on copper's function in angiogenesis, a critical stage in the formation of cancer (30,31,32). A lot of this research focused on copper's influence on angiogenesis, a critical mechanism for the development of cancer, and found higher Cu levels in a variety of human neoplasms, including breast cancer and lymphoma (14). ...
Objective: The complex disease of colon cancer is impacted by a number of genetic, dietary, and environmental variables. This article investigates the role of heavy metals and trace elements in colon cancer growth pathways. The critical role that trace elements play in numerous physiological processes is the main reason that their presence has such a significant impact on how the body functions.
Material and Methods: In a cross-sectional investigation that was conducted from August 2022 to January 2023, zinc (Zn), manganese (Mn), calcium (Ca) , chromium (Cr), copper (Cu), lead (Pb), sodium (Na), magnesium (Mg), selenium (Se), mercury (Hg),potassium (K), and iron (Fe) levels were measured in CRC cases.
Results: The average age of the people in the study group was 77.4 ± 28.1. The median level of K, Hg, Cu, and Fe in cancerous tissues was significantly increased than that of healthy tissues (P <0.05). Still, the median of Zn, Cr, Mn, Pb, Na, Se, and Ca was much lower in cancerous tissues (P <0.05) than in non-cancerous tissues.
Conclusion: We found that the amount of some trace elements may depend on the person's gender and how long they have smoked. We found that the amounts of eight elements were much different in cancerous tissues than in healthy ones.
... On the other hand, they can also stimulate cell migration. Copper is an essential cofactor for several enzymes involved in processes, such as tumor angiogenesis and wound healing [44,45]. So, cell cycle arrest is the primary mechanism by which many anticancer drugs inhibit tumor cell proliferation [46]. ...
Although chemotherapy has increased the life expectancy of cancer patients, its toxic side effects remain a major challenge. Recently, organometallic compounds, such as Schiff base copper complexes, have become promising candidates for next-generation anticancer drugs owing to their unique anticancer activities. In this study, binuclear copper(II) complex-1 and mononuclear copper(II) complex-2 were examined to analyze their anticancer mechanisms further. For this purpose, a viability test, flow cytometry analysis of apoptosis and the cell cycle, migration assay, and gene expression analysis were performed. According to our results, complex-1 was more cytotoxic than complex-2 at 24/48-h intervals. Our findings also demonstrated that both complexes induced apoptosis at IC50 concentrations and arrested the cell cycle at the G1-S checkpoint. However, complex-1 accelerates cell cycle arrest at the sub-G0/G1 phase more than complex-2 does. Furthermore, gene expression analysis showed that only complex-1 induces the expression of p53. Interestingly, both complexes induced Bcl-2 overexpression. However, they did not affect MMP-13 expression. More interestingly, both complexes inhibited cell migration in different ways, including amoeboid and collective, by recruiting protease-independent pathways. This study confirmed that adding several metal cores and co-ligands increased the activity of the complex. It also appeared that Cu-containing complexes could prevent the migration of cancer cells through protease-independent pathways, which can be used for novel therapeutic purposes.
... Specifically, due to the proven angiogenic potential of Cu ions, high doses of Cu ions favour tumour growth. Numerous studies have shown elevated Cu values in tumour tissue as evidence for this claim [13,14]. Contrarily, the molecular mechanisms of Cu-complexes are based on covalent binding to the DNA of cancer cells. ...
Due to the unique functional properties of shape memory alloys (SMAs) and current scientific interest in Cu-containing biomaterials, a continuously cast Cu-Al-Ni alloy in the form of rods has been investigated as a potential candidate for biomedical application. Additionally, the fact that Cu- complexes have an antitumour effect served as a cornerstone to develop more efficient drugs based on trace element complexes. In line with that, our study aimed to analyse the basic properties of the Cu-Al-Ni alloy, along with its anticancer properties. The detailed chemical analysis of the Cu-Al-Ni alloy was performed using XRF and SEM/EDX analyses. Furthermore, a microstructural and structure investigation was carried out, combined with hardness measurements using the static Vickers method. Observations have shown that the Cu-Al-Ni microstructure is homogeneous, with the presence of typical martensitic laths. XRD analysis confirmed the presence of two phases, β′ (monoclinic) and γ′ (orthorhombic). The viability of osteosarcoma cells in contact with the Cu-Al-Ni alloy was evaluated using epifluorescence microscopy, while their morphology and attachment pattern were observed and analysed using a high-resolution SEM microscope. Biocompatibility testing showed that the Cu-Al-Ni alloy exerted a considerable antineoplastic effect.
... An intake of 900 µg per day is recommended for this essential trace element, while a level of 10 mg per day is the maximum permissible (28). Excess copper may promote radical damage and decrease the activity of proteins or enzymes, thus causing cellular injury via overactivated oxidative stress, lipid peroxidation, inflammation, and DNA damage, finally helping in the angiogenesis of tumors (29). It remains controversial whether copper intake contributes to EC prevention, despite many studies focusing on the relationship between copper intake and the disease. ...
Numerous epidemiological and laboratory studies on essential trace elements have reported protective associations in developing various cancer types, including esophagus cancer (EC). However, the results are not always consistent. Some essential trace elements could play a vital role in preventing esophagus cancer. Some showed no association with esophageal cancer risk, while others harmed individuals. This article reviews the association between the intake or supplementation of essential trace elements (especially zinc, copper, iron, and selenium) and the risk of esophageal cancer. Generally, zinc intake may decrease the risk of esophageal cancer (EC), especially in high esophageal squamous cell carcinoma (ESCC) prevalence regions. The association between copper supplementation and EC remains uncertain. Total iron consumption is thought to be associated with lower EC risk, while heme iron intake may be associated with higher EC risk. Selenium intake showed a protective effect against EC, especially for those individuals with a low baseline selenium level. This review also prospects the research direction of the association between EC and essential trace elements.
... The clinical relevance of copper complexes in cancer oncology is primarily attributed to the differential response and altered metabolism demonstrated by the cancerous cells in response to copper [15]. The elevated serum copper levels display a strong correlation with the tumour progression and recurrence of diverse cancers, including lung, liver, breast, Hodgkin's lymphoma etc. [16,17]. Cobalt features as an essential trace element present in the active site of vitamin B 12 and offers a specific role in the normal functioning of nervous tissue, haematopoiesis (blood formation) and DNA synthesis [18]. ...
In the present work, we report the synthesis, structural characterization and in vitro biological evaluation of four mononuclear Cu(II) and Co(II) complexes 1–4 derived from the Schiff base ligand scaffolds L1 and L2. The synthesized complexes 1–4 were systematically characterized by various analytical and spectroscopic techniques (FTIR, EPR, UV–vis and sXRD). DFT calculations were performed to determine the structural, electronic and chemical properties of complexes 1–4 based on their respective HOMO and LUMO energy values. Hirshfeld surface analysis was carried out to examine the intermolecular interactions (CH···O, NH···H, Cl–H···H and OH···O) which define the stability of the crystal lattice. Furthermore, comparative in vitro DNA/BSA binding studies were carried out by employing various biophysical methods which revealed a higher binding propensity for the copper analogues. The antioxidant activity of complexes 1–4 was also evaluated against the free radical DPPH and the results demonstrated a better radical scavenging activity by the copper analogues. In addition, the cytotoxicity of the complexes was evaluated using an SRB assay against MDA–MB–231/HCC1806 (triple negative breast cancer cell lines) and HT–29 (colorectal cancer cell lines), which revealed remarkable cytotoxicity of complex 3 against the tested cancer cell lines. The toxicity profile of the complexes was also evaluated against VERO (normal kidney epithelial) cells, which validated their low toxicity behaviour.
... Among micronutrients and trace elements, copper plays an essential role in tumorigenesis [1,23] and has emerged as a critical factor in angiogenesis [3,8,39]. Thus, using copper chelators that minimize the cellular copper availability represents a promising strategy in cancer therapy to attenuate, or even block, the aggressive angiogenesis found in tumors [40,41]. While a range of copper chelating agents have been described [11,22,42], their selectivity is often insufficient, as they can chelate other essential d-block metal ions, such as Fe 2+ or Zn 2+ . ...
Human lung cancer ranks among the most frequently treated cancers worldwide. As copper appears critical to angiogenesis and tumor growth, selective removal of copper represents a promising strategy to restrict tumor growth. To this end, we explored the activity of the novel high-affinity membrane-permeant Cu(I) chelator PSP-2 featuring a low-zeptomolar dissociation constant. Using H460 human lung cancer cells, we generated small tumors on the chorioallantoic membrane of the chicken embryo (CAM assay) and studied the effects of topical PSP-2 application on their weight and vessel density after one week. We observed a significant angiosuppression along with a marked decrease in tumor weight under PSP-2 application compared to controls. Moreover, PSP-2 exposure resulted in lower ki67+ cell numbers at a low dose but increased cell count under a high dose. Moreover, HIF-1α+ cells were significantly reduced with low-dose PSP-2 exposure compared to high-dose and control. The total copper content was considerably lower in PSP-2 treated tumors, although statistically not significant. Altogether, PSP-2 shows promising potential as an anti-cancer drug. Nevertheless, further animal experiments and application to different tumor types are mandatory to support these initial findings, paving the way toward clinical trials.
... Cu has been shown to increase proliferation of endothelial cells and in vivo angiogenesis. In the clinical settings, physicians have attempted to reduce angiogenesis of tumors by restricting Cu intake [40]. Recently, Wu et al., incorporated Cu into ceramic scaffolds and showed that the release Cu ions induced hypoxia inducible factor-1α secretion from MSC, thus promoting expressions of various angiogenic-related proteins [41]. ...
Numerous studies have demonstrated that biological compounds and trace elements such as dopamine (DA) and copper ions (Cu) could be modified onto the surfaces of scaffolds using a one-step immersion process which is simple, inexpensive and, most importantly, non-cytotoxic. The development and emergence of 3D printing technologies such as selective laser melting (SLM) have also made it possible for us to fabricate bone scaffolds with precise structural designs using metallic compounds. In this study, we fabricated porous titanium scaffolds (Ti) using SLM and modified the surface of Ti with polydopamine (PDA) and Cu. There are currently no other reported studies with such a combination for osteogenic and angiogenic-related applications. Results showed that such modifications did not affect general appearances and microstructural characteristics of the porous Ti scaffolds. This one-step immersion modification allowed us to modify the surfaces of Ti with different concentrations of Cu ions, thus allowing us to fabricate individualized scaffolds for different clinical scenarios. The modification improved the hydrophilicity and surface roughness of the scaffolds, which in turn led to promote cell behaviors of Wharton’s jelly mesenchymal stem cells. Ti itself has high mechanical strength, therefore making it suitable for surgical handling and clinical applications. Furthermore, the scaffolds were able to release ions in a sustained manner which led to an upregulation of osteogenic-related proteins (bone alkaline phosphatase, bone sialoprotein and osteocalcin) and angiogenic-related proteins (vascular endothelial growth factor and angiopoietin-1). By combining additive manufacturing, Ti6Al4V scaffolds, surface modification and Cu ions, the novel hybrid 3D-printed porous scaffold could be fabricated with ease and specifically benefited future bone regeneration in the clinic.
... Une diminution de concentration sérique du cuivre dans les patients cancéreux sous traitement chimiothérapie pour la population algérienne ; les raisons de la baisse des taux des taux de cuivre, ils ont été montrés que les taux diminuent après le traitement contre le cancer et augmentent avant la rechute. [213] Dans le contexte des maladies cancéreuses, le rôle du cuivre dans l'angiogenèse tumorale a été démontré, et la réduction du taux de cuivre chez les patients cancéreux est devenue l'une des approches des traitements anti-angiogéniques [214] Puisque le Zn et le Cu pourraient entrer en compétition dans l'intestin grêle, si l'un d'eux augmente ou diminue, cela interférerait avec l'absorption de l'autre [215]. les différences entre les genres dans la détection précoce peuvent également être un facteur contributif [220]. ...
Zinc, copper and iron are among the essential minerals in the body with direct impact in cancer. This study aims to assess the concentrations of these trace elements in the blood samples from Algerian cancer patients compared to healthy subjects. Blood samples taken for cancer patients at the Blida University Hospital
"France Fanon" oncology department. Where it transferred to the laboratory of fundamental and applied physics to use nuclear technology to analyze the samples, which is X-ray fluorescence. This done after the samples treated chemically with wet digestion to remove the organic part from the blood. Then, the ANOVA OneWay
test applied to the statistical analysis.
Analysis the concentration of iron with the X-ray fluorescence technique in the blood of 80 patients and 98 healthy subjects gave a mean concentration of 1496 µg/l for patients with 1493 µg/l for healthy subjects. After the statistical comparison of these results, it expressed that there was no difference between the mean concentrations in the two groups for iron. The same samples were analyzed of zinc and copper. The concentrations for patients and healthy subjects were zinc: 1344 µg/l and 1266 µg/l, respectively. Copper: 1078 and 1172 µg/l and there was a significant difference between them (p> 0.05).
The concentrations of patients and healthy subjects of copper for the two genders are respectively, 1201 and 1085 µg/l for women and 1148 and 1070 µg/l for men. As for zinc 1310 and 1325 µg/l for women and 1231, 1368 µg/l for men.
Statistical analysis of the two trace elements in both genders showed that there was a significant decrease in women compared to copper, unlike zinc, a significant increase was observed in men.
In addition, we were able to express the relationship between age and the rate of trace element concentrations in an experimental equation.
We have also studied the levels of trace elements in patients with lung cancer in particular and in healthy smokers and non-smokers. There is a relative relationship between the concentration of smokers and lung cancer patients compared to healthy non-smokers.
... The background of correlation between copper levels and cancer formation derives from the hypothesis that alterations in micronutrients seem to change the oxidative response of cells, and may be prone to malignant transformation. Increased copper levels are known to play a signifi cant role in reactive oxygen species (ROS), and endothelial proliferation causing angiogenesis (5,6). These two factors are well known prerequisites of cancer formation and proliferation, thus safely assuming that copper can play a central role in this process (7). ...
Wilson's Disease (WD) is a rare autosomal recessive hereditary disease with copper accumulation in the body, particularly the liver, brain and cornea. WD is widely treated with chelation agents who enable the copper excretion. Since high concentrations of copper are toxic, WD is associated with hepatocellular carcinoma and cholangiocarcinoma, with low incidence of other types of cancer. We present a case of a 33 year old man who was treated in the Oral and Maxil-lofacial Surgery Department of the Aristotle University of Thessaloniki with multiple dysplasia lesions and an in situ carcinoma of the tongue, which is to our knowledge the fi rst case report of oral lesions to a patient with WD. Literature is reviewed on copper levels on patients with head and neck cancer, and on chelation agents and their effect on cancer cells.
... Copper plays an important role in angiogenesis and can stimulate endothelial cell proliferation in a variety of benign and malignant conditions. [1][2][3] Experimental and human studies have demonstrated that the copper metabolism is altered in several malignancies. 4 The presence of high amounts of copper in neoplastic tissues has been considered as the rationale for the use of copper as an imaging biomarker for PET imaging. ...
Purpose of the report:
The aim of this study was to evaluate safety and efficacy of copper-64(II)dichloride (64Cu(II)Cl2) as a new PET tracer for urological malignancies (UMs).
Methods:
Patients with UM were enrolled in a prospective study. All patients were staged with preoperative CT and 64Cu(II)Cl2 PET/CT. Patient characteristics, anatomical and functional imaging, and final histopathology were recorded. Surgical specimens for histopathological examination were collected. To determine time-activity curves for 64Cu(II)Cl2 uptake in UM and normal tissues, SUVs were calculated. The safety of 64Cu(II)Cl2 was assessed.
Results:
Twenty-three patients were included. An administered activity of 174.7 MBq (4.72 mCi) for 64Cu(II)Cl2 was equal to 9.80 mSv of the effective dose. The median SUVmax values were 5.7, 0.9, 1.8, and 9.8 for the prostate, bladder, penis, and kidney, respectively. Median SUVmax values were higher in organs with a malignancy in comparison with healthy tissue (prostate [11.5 vs 5.3, P < 0.001], bladder [6.2 vs 0.9, P = 0.007], and penis [3.9 vs 1.3, P = 0.027]), but not in the kidneys (5.0 vs 10.4, P = 0.998). The highest area under the curve (AUC) was reported for prostate cancer (AUC, 0.978), and the lowest for penile cancer (AUC, 0.775). The detection rates based on the best suggested cutoff according to the SUVmax were 85.7% (6/7) for prostate and bladder and 83.3% (5/6) for penile cancer. Neither drug-related effects nor physiologic responses occurred, nor adverse reactions.
Conclusions:
64Cu(II)Cl2 is an effective and well-tolerated tracer in patients with UM. Our results show higher SUVmax in cancer patients than in healthy subjects. Our findings suggest that 64Cu(II)Cl2 PET/CT is useful in patients affected by prostate, bladder, and penis cancer.
... High content of copper (5 mg daily) is released within 5-15 min of chewing areca nut which induces upregulation of lysyl oxidase which, in turn, increases fibroblasts activity, [2] Opsahl et al. reported that lysyl oxidase activity varies by as much as five-to six-fold in response to dietary copper, ...
To date, no treatment strategies for oral submucous fibrosis (OSMF) have been proved to be completely effective, and one of the most accepted medical lines of therapy advised in every stage of OSMF is antioxidants. One of the antioxidant drugs has increasingly earned popularity, which is due to its less expensive market price than other available antioxidants formulations. The presence of copper in its composition questions its ability to be effective in the management of OSMF. Moreover, we would like to emphasize that the presence of copper adds on to the disease burden and antioxidants with copper in its composition should not be advised as an antioxidant of choice for the management of OSMF.
... However, the role of Cu in angiogenesis differs from that in osteogenesis, in which Cu ions are essential in novel biomaterials designed to facilitate vessel formation [28,43,51]. Moreover, Cu 2+ has been shown as necessary for endothelial cell activation in the early stage of angiogenesis [43,52]. As demonstrated in the CCK-8 assay (Fig. 2B), HUVECs of 1.0Cu-HA proliferated faster than those of CPS (P < 0.001 at day 5), which was consistent with the immunofluorescence finding (Fig. 4C). ...
Promoting bone regeneration to treat bone defects is a challenging problem in orthopedics, and developing novel biomaterials with both osteogenic and angiogenic activities is sought as a feasible solution. Here, copper-silicocarnotite [Cu–Ca5(PO4)2SiO4, Cu-CPS] was designed and fabricated. In this study, the Cu-CPS ceramics demonstrated better mechanical, osteogenic, and angiogenic properties in vitro and in vivo than pure CPS one. Particularly, CPS with 1.0 wt% CuO (1.0Cu-CPS) exhibited the best performance. Additionally, hydroxyapatite with 1.0 wt% CuO (1.0Cu-HA) was used to explore the respective effects of copper and silicon (Si). According to the in vitro results, it indicated that Cu enhanced the osteogenic activity of CPS ceramics although Si played a dominate role in the osteogenic process. Moreover, Cu could promote an early stage of angiogenesis, and the complementary effect of Si and Cu was found in the late phase. Furthermore, the in vivo results illustrated that the synergistic effect of Cu and Si improved bone and vessel regeneration during the degradation of Cu-CPS scaffolds (P < 0.05). Therefore, Cu-CPS ceramics could improve osteogenesis and angiogenesis through the simultaneous effects of Cu and Si, thus, offering a promising treatment option in orthopedic application for bone tissue regeneration.
... It can also enhance its affinity for endothelial cells [95,96]. It is the only transition metal found to be a cofactor required for several angiogenic mediators including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), interleukin 1 (IL-1), and IL-8 [97][98][99]. Moreover, copper is involved in the regulation of the secretion of angiogenic molecules such as fibroblast growth factors (FGFs) and IL-1α [100]. ...
Zinc (Zn) and copper (Cu) are essential microelements, which take part in cellular metabolism, feature in enzymatic systems, and regulate enzyme activity. Homeostasis of these micronutrients is tightly regulated by multiple compensatory mechanisms that balance their concentrations including transporters, importers, and metallothioneins. An altered intake of only one of these trace elements may cause an imbalance in their levels and result in their competition for absorption. Relatively low levels of zinc and increased levels of copper may result in an increased level of oxidative stress and impair the antioxidant properties of multiple enzymes. Altered levels of trace elements were discovered in various pathologies including immunological, degenerative, and inflammatory diseases. Moreover, due to the role of Zn and Cu in oxidative stress and chronic inflammation, they were found to influence cancerogenesis. We review the roles of zinc and copper and their mechanisms in tumor growth, metastasis potential, microenvironment remodeling, and drug resistance. We highlight their role as potential biomarkers for cancer diagnosis, treatment, and prognosis, concentrating on their impact on gynecological malignancies.
... Modifications of Cu concentration and relative abundance of Cu isotopes (fractionation) have been linked to modified metabolic processes (oxidative phosphorylation, hypoxia) or in angiogenesis, and thus to health and disease 92 . In different cancers it has been shown that copper is required for angiogenic processes 93 , stimulating proliferation and migration of endothelial cells 94 . In the liver tissue of colon tumour bearing mice, gene expression the copper transporters ceruloplasmin, and CTR1 and ATP7B was increased significantly, which can explain elevated copper serum levels 95 and suggesting its potential use as a diagnostic marker of cancer. ...
Ovarian cancer is the seventh most common cancer in women with five-year survival rates of less than 45%, and only 20% of cases are detected at early stages of the disease. Major challenges still exist to treat this lethal disease.The development of new drugs that target better cancer cells and reduce side effects is highly needed. Selenium at high doses has been shown to act as a cytotoxic agent, with potential applications in cancer treatment. However, clinical trials have failed to show any chemotherapeutic value of selenium at safe and tolerated doses (<90 g/day). To enable the successful exploitation of selenium for cancer treatment, I evaluated inorganic selenium nanoparticles (SeNP), and found them effective in inhibiting ovarian cancer cell growth. In both SKOV-3 and OVCAR-3 ovarian cancer cell lines SeNP treatment resulted in significant cytotoxicity. The two cell types displayed contrasting nanomechanical responses to SeNPs, with decreased surface roughness and membrane stiffness characteristic of OVCAR-3 cell responses. In SKOV-3, cell membrane surface roughness and stiffness increased, both are properties associated with decreased metastatic potential. Very excitingly I made the novel discovery that SeNPs dramatically increase histone methylation at three histone marks, namely H3K4, H3K27 and H3K9. This effect was partially blocked by pharmacological agents that blocked histone methyltransferase (HMT) function. Gene expression profiling of SeNP treated cells demonstrated that Se caused changes in the expression of HMTs suggesting one mechanism for its ability to alter histone methylation. Further interrogation of RNA seq data showed the SeNPs impact on the expression of genes linked to hallmarks of cancer such as DNA repair activation, ROS response, extracellular matrix organization. The beneficial effects of SeNPs on ovarian cancer cell death appear to be cell type dependent, and due to their low in vivo toxicity, offer an exciting opportunity for future cancer treatment.Finally, following on from recent studies in breast and colorectal cancer patients revealing that measurement of circulating copper isotopes (63Cu/65Cu ratio) can be related to cancer development I investigated this in clinical ovarian cancer samples (blood and tissue). A significant decrease in copper isotopic ratios in the serum of cancer donors was observed demonstrating the potential effectiveness of 63Cu/65Cu for the blood-based detection of ovarian cancer.
While some metals have been reported as carcinogens or potential carcinogens, only few modern-standard datasets including a large number of elements are available. The present analysis established a first trace elements spectrum by relating the concentration of metals and trace elements in the serum of sarcoma patients with survival data.
Patients with sarcoma and controls were retrospectively selected from the International Sarcoma Kindred Study database (ISKS). As part of the ISKS study, blood samples were prospectively collected at the Leon Bérard Cancer Center from February 2012 to July 2019. Stable specimens and copper isotopes (65Cu/63Cu) were analyzed using Triple Quadrupole Inductively Coupled Plasma Mass Spectrometer (ICP-MS) and the Multicollector MC-ICP-MS Nu Plasma HR 500. Wilcoxon rank sum test, log-rank test, and multivariate Cox regression models were used for statistics.
In total, 151 patients and 59 healthy controls were included. At the time of blood sample collection, 62% of patients had locally advanced or metastatic disease. Copper (Cu), copper/zinc (Cu/Zn) and potassium/rubidium (K/Rb) ratio were significantly higher in patients compared to controls and were also significantly higher in patients with advanced compared to early-stage sarcoma. Whereas S and Se were significantly correlated in patients, no correlation was observed in controls. Importantly, levels of K, Rb, Se, Fe, P, Si, S, δ65Cu, Cu, S/Se and Cu/Zn ratio were independently associated with overall survival.
These results depict the metallomic spectrum in sarcoma and highlight substantial variation associated with survival, enhancing our understanding of sarcoma’s biology.
Cuproptosis, a newly identified copper (Cu)-dependent form of cell death, stands out due to its distinct mechanism that sets it apart from other known cell death pathways. The molecular underpinnings of cuproptosis involve the binding of Cu to lipoylated enzymes in the tricarboxylic acid cycle. This interaction triggers enzyme aggregation and proteotoxic stress, culminating in cell death. The specific mechanism of cuproptosis has yet to be fully elucidated. This newly recognized form of cell death has sparked numerous investigations into its role in tumorigenesis and cancer therapy. In this review, we summarized the current knowledge on Cu metabolism and its link to cancer. Furthermore, we delineated the molecular mechanisms of cuproptosis and summarized the roles of cuproptosis-related genes in cancer. Finally, we offered a comprehensive discussion of the most recent advancements in Cu ionophores and nanoparticle delivery systems that utilize cuproptosis as a cutting-edge strategy for cancer treatment.
o‐Aminoazotoluene (OAT), capable of photoisomerization, and o‐vanillin, a potent comutagen, have been used to synthesize a new ligand, HL, [C6H4(CH3)N=NC6H3(CH3)N=CHC6H3(OH)(OCH3)], which, upon complexation with copper(II), results in a new copper(II) complex‐Cu(L)2, [Cu{C6H4(CH3)N=NC6H3(CH3)N=CHC6H3(OCH3)O}2]. Both HL and Cu(L)2 have been characterized by single‐crystal X‐ray diffraction measurements along with other analytical techniques, for example, IR spectroscopy, NMR spectroscopy, UV–Vis spectroscopy, elemental analysis and mass spectrometry. These compounds were tested with different in vitro anticancer assay as well as with in silico studies. A comparative study has been demonstrated on anticancer activity of HL and Cu(L)2 with the ligand HAZ, {C6H5N=NC6H4N=CHC6H3(OH)(OCH3)} and its Cu‐complex, [Cu(AZ)2, Cu{C6H5N=NC6H4N=CHC6H3(OCH3)O}2]. The sensing properties of HAZ, along with the synthesis and structural properties of both HAZ and Cu(AZ)2, have been reported by our group earlier. Cytotoxicity measurements on MCF7 cell lines show that Cu(L)2 and Cu(AZ)2 have higher anticancer activity than their corresponding ligands. The apoptotic effect of Cu‐complex was studied through nuclear fragmentation assay and AO/EB dual‐staining assay on MCF7 cell line. The IC50 value of Cu(L)2 in 0.01% DMSO/water after 24‐h treatment was found 4.2 μM, which is one of the lowest values with this response time compared to the other analogous anticancer compounds. Finally, we have evaluated the expression of hERα protein with respect to Cu‐complexes, and it was observed that Cu(L)2 caused more down‐regulation of hERα as compared to Cu(AZ)2.
Peri-implant lesion is a grave condition afflicting numerous indi-viduals with dental implants. It results from persistent periodontal bacteria accumulation causing inflammation around the implant site, which can primarily lead to implant loosening and ultimately the implant loss. Early-stage peri-implant lesions exhibit symptoms akin to gum disease, including swelling, redness and bleeding of the gums surrounding the implant. These signs indicate infection and inflammation of the peri-implant tissues, which may result in bone loss and implant failure. To address this problem, a thermionic strategy was applied by designing a cuprorivaite–hardystonite bioceramic/alginate composite hydrogel with photothermal and Cu/Zn/Si multiple ions releasing property. This innovative approach creates a thermionic effect by the release of bioactive ions (Cu2+ and Zn2+ and SiO32−) from the composite hydrogel and the mild heat environment though the photothermal effect of the composite hydrogel induced by near-infrared light irradiation. The most distinctive advantage of this thermionic effect is to substantially eliminate periodontal pathogenic bacteria and inhibit inflammation, while simultaneously enhance peri-implant osseointegration. This unique attribute renders the use of this composite hydrogel highly effective in significantly improving the survival rate of implants after intervention in peri-implant lesions, which is a clinical challenge in periodontics. This study reveals application potential of a new biomaterial-based approach for peri-implant lesion, as it not only eliminates the infection and inflammation, but also enhances the osteointegration of the dental implant, which provides theoretical insights and practical guidance to prevent and manage early-stage peri-implant lesion using bioactive functional materials.
Imaging techniques permit the study of the molecular interactions that underlie health and disease. Each imaging technique collects unique chemical information about the cellular environment. Multimodal imaging, using a single probe that can be detected by multiple imaging modalities, can maximise the information extracted from a single cellular sample by combining the results of different imaging techniques. Of particular interest in biological imaging is the combination of the specificity and sensitivity of optical fluorescence microscopy (OFM) with the quantitative and element-specific nature of X-ray fluorescence microscopy (XFM). Together, these techniques give a greater understanding of how native elements or therapeutics affect the cellular environment. This review focuses on recent studies where both techniques were used in conjunction to study cellular systems, demonstrating the breadth of biological models to which this combination of techniques can be applied and the potential for these techniques to unlock untapped knowledge of disease states.
A novel chiral oxazoline copper(II)-based complex {[Cu(C13H14NO3S)2]}2 (Cu-A) was synthesized by an in situ reaction using L-methioninol, 4-hydroxyisophthalaldehyde, sodium hydroxide and copper(II) nitrate trihydrate as reactants. Its crystal structure was characterized. In vitro, Cu-A was superior to cis-dichlorodiammineplatinum (DDP) in cytotoxicity and angiogenesis inhibition. Cu-A significantly induced apoptosis of ovarian cancer cells (SKOV3) and human umbilical vein endothelial cells (HUVECs), showing significant anti-ovarian cancer and anti-angiogenesis effects. Notably, Cu-A significantly inhibits the growth of ovarian cancer in nude mice xenografted with SKOV3 cells, and it is less renal toxic than DDP. The molecular mechanism of anti-ovarian cancer and anti-angiogenesis is possibly that it down-regulates the expression of the proteins ERK1/2, AKT, FAK, and VEGFR2 and their phosphorylated proteins p-ERK1/2, p-AKT, p-FAK, and p-VEGFR2 in the VEGF/VEGFR2 signal transduction pathway to inhibit SKOV3 cell and HUVEC proliferation, induce apoptosis, suppress migration and metastasis, and inhibit angiogenesis. What's more, Cu-A significantly inhibits ovarian tumor growth in vivo by inhibiting tumor cells from inducing vascular endothelial cells to form their own vasculature and by inhibiting the expression of the anti-apoptotic protein Bcl-2 and up-regulating the expression of the pro-apoptotic proteins Caspase-9 and Bax to induce apoptosis of tumor cells.
Background:
A variety of dietary adjuncts are known to affect the pathophysiology of glioma, making them a potential therapeutic adjunct to standard of care. We systematically reviewed clinical outcomes in glioma patients treated with one or more nutritional adjunct and/or an antimetabolite drug.
Methodology:
A systematic review of the literature following PRISMA guidelines was performed using Pubmed from inception till February 2023. In total, 22 manuscripts on nutrition representing 828 patients were included in the review. Statistical analyses were performed to compare the outcomes of various adjuncts.
Results:
The median overall survival (OS) increased for newly diagnosed (21 months) and recurrent cases (10 months) when compared to historical data. For newly diagnosed cases, a ketogenic diet had the highest median OS of all the adjuncts (42.6 months) while in recurrent cases, a low copper diet coupled with 1 g penicillamine had the highest median OS (18.5 months). However, no statistically significant difference was observed in OS or progression-free survival (PFS) of newly diagnosed or recurrent gliomas.
Conclusion:
While nutritional adjuncts may offer a therapeutic benefit in the treatment of glioma, more human subject research is needed to derive meaningful conclusions.
Oral submucous fibrosis (OSF) is a potentially malignant disorder, chiefly caused by areca nut consumption. Development of OSF involves a complex balance involving a multitude of molecules and enzymes. Several reported studies have assessed the influence of dietary factors on the etiopathogenesis of OSF. Low dietary fibre, high levels of copper, low levels of micronutrients including Zinc, Iron, Selenium, Vitamins A, B, C, and E have been observed in OSF. Dietary supplementation of these micronutrients in OSF has been shown to improve signs and symptoms of the disease.KeywordsCopperDietMicronutrientsOSFVitamins
The significantly increased copper level in tumor tissues and serum indicates the close association of copper ions with tumor development, making copper ions attractive targets in the development of novel tumor treatment methods. The advanced nanotechnology developed in the past decades provides great potential for tumor therapy, among which Cu‐based nanotherapeutic systems have received greater attention. Herein, the multifaceted roles of copper ions in cancer progression are summarized and the recent advances in the copper‐based nanostructures or nanomedicines for different kinds of tumor therapies including copper depletion therapy, copper‐based cytotoxins, copper‐ion‐based chemodynamic therapy and its combination with other treatments, and copper‐ion‐induced ferroptosis and cuproptosis activation are discussed. Furthermore, the perspectives for the further development of copper‐ion‐based nanomedicines for tumor therapy and clinic translation are presented by the authors.
This study aimed to establish that copper‐deposited Diatom‐biosilica have the potential and possibility for clinical applications in repairing bone defects in a state of inflammation, such as periodontitis. Treatment of alveolar bone defects caused by periodontitis is a major challenge for clinicians. To achieve better repair results, the material should not only be bone conductive but also have the ability to stimulate osteogenesis and angiogenesis at the lesion site. Copper (II) and silicon (IV) ions could react to form basic copper silicate, which promoted both osteogenesis and angiogenesis. The mineralized diatom (Cu‐DBs) loaded with copper (II) ions were synthesized by processing diatom shells using a hydrothermal method. Periodontal ligament stem cells (PDLSCs) are used to detect the osteogenic properties of Cu‐DBs at the gene and protein levels. Using a rat cranial defect model and a full‐thickness skin incision model to test the osteogenic properties of Cu‐DBs in vivo. Compared with untreated diatoms (DBs), Cu‐DBs extract significantly promoted the expression of osteogenesis‐related factors like ALP, RUNX2, BSP, OCN, and OPN in PDLSCs. In vivo experiments further confirmed that Cu‐DBs could effectively stimulate the osteogenesis of a rat skull defect and promote angiogenesis, significantly inhibit the inflammatory responses to bone damages, and reduce the infiltration of inflammatory immune cells to the lesion site. Due to the unique chemical characteristics of Si⁴⁺ and Cu²⁺ ions, the Cu‐DBs composite biomaterial could enhance the osteogenic differentiation of PDLSCS in vitro, as well as stimulate the osteogenesis of the rat in vivo.
CYP2C and CYP3A cytochromes are induced by a variety of compounds and affect the pharmacokinetics and pharmacodynamics of a large number of drugs. Currently, the possibility of using copper coordination compounds in antitumor therapy is being actively studied. Evaluation of potential interactions between new molecules and P450 cytochromes is necessary at an early stage of drug design. The aim . To study the modulating effect of Cu(II) complexes with enamine and tetrazole derivatives on CYP2C9, CYP2C19 and CYP3A4 and their cytotoxic and antiproliferative properties on normal human lung fibroblasts MRC-5 and a 3D model of hepatocellular carcinoma HepG2. Materials and methods . Cytotoxic and antiproliferative activities of copper(II) complexes – [CuL2] (1), [Cu2(bipy)2(PT)4] (2), [Cu2(phen)2(PT)4] (3), {[Cu(phen)(MT)2]∙H2O}n (4) (L – anion of 2-anilinomethylidene-5,5-dimethylcyclohexane-1,3-dione; PT – 5-phenyltetrazolate anion; MT – 5-methyltetrazolate anion; bipy – 2,2’-bipyridine; phen – 1,10-phenanthroline) – were examined in 2D and 3D models using fluorescence-based phenotypic screening. The modulating effect on CYP2C9, CYP2C19 and CYP3A4 was studied using fluorescence-based targeted screening. The results of CYP3A4 expression were confirmed by real-time reverse transcription polymerase chain reaction (RT-PCR). Results . Complex (1) increases the CYP3A4 expression and does not affect CYP2C9 and CYP2C19 expression. Complex (2) has no modulating effect on CYP2C and CYP3A. Complexes with 1,10-phenatrolin (3) and (4) induce CYP3A4, inhibit CYP2C9 and do not affect CYP2C19 expression. All compounds have a dose-dependent cytotoxic effect on HepG2 and MRC-5: the compound with 5-methyltetrazolate anion (4) has the same effect on cell lines, compounds with 5-phenyltetrazolate anion (2) and (3) have selective effect. Complexes with 1,10-phenatrolin are effective on both 2D and 3D models. Conclusion . The [Cu2(phen)2(FT)4] complex (3) can be used as a basis for creating an antitumor compound, but further modification of the structure is required to increase the selectivity to tumor cells.
Areca nut (AN) is the fourth most widely used addictive substance and chewed regularly by at least 10% of the world population. AN cause many harmful effects on the human body in general as well as in the oral cavity. Amongst this one of the vital organs being damaged due to AN consumption is liver for which a number of mechanisms are reported to be responsible. Frequently alkaloids in AN are considered as the main culprit. But, other components like copper (Cu) content in AN is also believed to play a role in the pathogenesis of liver fibrosis. It is stated that an adult Indian chewing AN daily consumes over 5 mg of Cu per day, of which the substantial amount is absorbed. However, the recommended intake per day is 0.9 mg. Excess Cu acts by upregulating lysyl oxidase activity, which enhances collagen synthesis and inhibits collagen degradation leading to fibrosis of tissues. Another reason for liver toxicity could be reactive oxygen species generated by Cu content in AN. Thus, it may be stated that Cu in AN can be one of the risk factors inducing liver damage. The present review highlights the role of Cu content of AN in the development of liver fibrosis.
Mammary neoplasms are the most common in female dogs, with high malignancy rates. Despite sharing many similarities with human breast tissues, the prevalence of this type of cancer in dogs are nearly three times higher. Taking that into account, this study aims to present preliminary results about chemical and structural changes occurring in samples of canine breast tumors. For this, we analyzed seven samples including normal, benign and malignant tissues, using micro X-ray fluorescence (μ-XRF) and Compton scattering technique. Our goal was to respectively map the spatial distribution of Fe, Cu and Zn and to determine the electron densities in selected regions of the samples. Results showed that Cu and Zn distributions were spatially correlated in normal tissues, with lower intensities in adipose regions and higher in the fibrous ones. Regarding benign neoplasms, both samples exhibited an increase in Cu intensity over the tumor area, however in different proportions. For the malignant ones, the presence of Fe was observed mostly in the tumor-adjacent regions. The electron density values obtained allowed to differentiate tissue structures, with generally higher density in tumorous regions and lower in adipose tissues.
Angiogenesis, the process of new blood vessel formation, is orchestrated by a series of chemical signals in the human body, leading to the growth, migration, and differentiation of endothelial cells (ECs) inside the wall blood vessels. During the last decade, nanomaterials' role in advancing or prohibiting angiogenesis has been well-studied; inorganic nanoparticles are among the most promising tools in regulating neovascularization. Physicochemical characteristics of nanosized materials determine their ability to stimulate or suppress the angiogenesis process. Apart from the nature of chemical elements, the particle size, shape, surface charge, and administrated concentrations are mentioned as decisive parameters in governing the fate of cellular and molecular mechanisms involved in the angiogenesis process. Nowadays, inorganic nanoscale materials are being utilized in imaging angiogenesis in both healthy and pathological conditions. Still, there are serious concerns about the potential toxicity of inorganic nanoparticles for the body, limiting their extensive usage in managing various diseases and disorders in which imbalance of angiogenesis is observed.
Background
Although various skin cancer detection devices have been proposed, most of them are not used owing to their insufficient diagnostic accuracies. Laser-induced plasma spectroscopy (LIPS) can noninvasively extract biochemical information of skin lesions using an ultrashort pulsed laser.
Objective
To investigate the diagnostic accuracy and safety of a real-time noninvasive in vivo skin cancer diagnostics utilizing non-discrete molecular LIPS combined with a deep neural network (DNN)-based diagnostic algorithm.
Methods
In vivo LIPS spectra were acquired from 296 skin cancers (186 BCCs, 96 SCCs and 14 melanomas) and 316 benign lesions in a multisite clinical study. The diagnostic performance was validated using 10-fold cross-validations.
Results
The sensitivity and specificity for differentiating skin cancers from benign lesions using LIPS and the DNN-based algorithm were 94.6% (95% CI: 92.0 – 97.2%) and 88.9% (95% CI: 85.5 – 92.4%), respectively. No adverse events, including macroscopic or microscopic visible marks or pigmentation due to laser irradiation, were observed.
Limitations
The diagnostic performance was evaluated using a limited dataset. More extensive clinical studies are needed to validate these results.
Conclusions
This LIPS system with a DNN-based diagnostic algorithm is a promising tool to distinguish skin cancers from benign lesions with high diagnostic accuracy in real clinical settings.
Recent studies found that unbalanced copper homeostasis affect tumor growth, causing irreversible damage. Copper can induce multiple forms of cell death, including apoptosis and autophagy, through various mechanisms, including reactive oxygen species accumulation, proteasome inhibition, and antiangiogenesis. Hence, copper in vivo has attracted tremendous attention and is in the research spotlight in the field of tumor treatment. This review first highlights three typical forms of copper’s antitumor mechanisms. Then, the development of diverse biomaterials and nanotechnology allowing copper to be fabricated into diverse structures to realize its theragnostic action is discussed. Novel copper complexes and their clinical applications are subsequently described.
This work features synthesis, structural characterization and biological evaluation of two Cu(II)/Co(II)–based complexes (1 and 2) synthesized from levofloxacin (lvXn) and bipyridyl ligands. The structural elucidation of complexes 1 and 2 was carried out by analytical, spectral (UV-vis, FTIR, EPR) and single crystal X–ray crystallographic techniques. The crystallographic details of complex 1 revealed a triclinic crystal system with P-1 space group and lattice parameters a = 10.32(7) Å, b = 11.75(8) Å, c = 14.85(9) Å, and α = 87.40°, β = 77.55°, γ = 66.26°. The DFT studies were performed to study the electronic structure and localization of HOMO and LUMO electron densities on the complexes. We have also performed comparative in vitro DNA/BSA binding studies of complexes 1 and 2 by multispectroscopic methods to evaluate the cytotoxic potential of synthesized complexes which revealed better binding potential of copper analogue. Furthermore, the cytotoxic assessment of copper analogue was examined on a panel of five human cancer cell lines employing SRB assay which revealed remarkably good and selective cytotoxic activity towards A498 (kidney), HeLa (cervical) and HepG2 (hepatoma) cancer cell lines.
Purpose
This investigation forms part of a wider study into the legacy effects of exposure of rainbow trout eggs 38h after fertilisation, eyed eggs, yolk sac larvae (YSL) or first feeders to a single 0.5 Gy X-ray dose, including the induction of a bystander effect, by the irradiated fish, to non-irradiated fish. Fish may be exposed to multiple environmental stressors, including waterborne metals, during their lifespan and, while there are data on how the legacy of early life stage irradiation and bystander effect induction is affected by waterborne aluminum and cadmium, there are no studies into the effects radiation or the radiation induced bystander effect on metal uptake. Therefore the aim of this investigation was to determine if the legacy of early life stage irradiation included an effect on copper uptake by adult fish and by non-irradiated bystander adult trout which swam with the irradiated fish.
Methods
The four early life stages mentioned above were exposed to a single 0.5 Gy X-ray dose and then maintained, for two years with no further irradiation. At two years old the irradiated fish were allowed to swim, for 2h with non-irradiated bystander trout (also two years old). After this time copper uptake was determined using ⁶⁴Cu.
Results
Copper uptake was increased in adult trout irradiated as eggs at 48h after fertilisation and as first feeders but eyed egg or YSL irradiation had no effect. Copper uptake was also increased in the bystander trout which swam with trout irradiated as eggs at 48h after fertilisation and as eyed eggs but there was no effect on non-irradiated adult trout which swam with trout irradiated as YSL or first feeders.
Conclusions
When put in context with the proteomic changes observed in these fish we propose the increased copper uptake in adult trout irradiated as eggs at 48h after fertilisation could be part of an anti-tumorigenic response and the increase in copper uptake in adult trout irradiated as first feeders could be part of a potentially protective pro-apoptotic response. Similarly we propose the increase in copper uptake in non-irradiated adult trout, induced by trout irradiated as eggs at 48h after fertilisation or as eyed eggs, was part of the universally anti-tumorigenic nature of the X-ray induced bystander effect in fish. However this was exclusive to embryonic irradiation.
Anticancer agents that present nonapoptotic cell death pathways are required for treating apoptosis-resistant pancreatic cancer. Here, we synthesized three fluorescent dithiocarbazate-copper complexes, {[CuII(L)(Cl)] 1, [CuII2(L)2(NO3)2] 2, and [CuII2CuI(L)2(Br)3] 3}, to assess their antipancreatic cancer activities. Complexes 1-3 showed significantly greater cytotoxicity toward several pancreatic cancer cell lines with better IC50 than those of the HL ligand and cisplatin. Confocal fluorescence imaging showed that complex 3 was primarily localized in the mitochondria. Primarily, compound 3 also can be applied to in vivo imaging. Further studies revealed that complex 3 kills pancreatic cancer cells by triggering multiple mechanisms, including ferroptosis. Complex 3 is the first copper complex to evoke cellular events consistent with ferroptosis in cancer cells. Finally, it significantly retarded the ASPC-1 cells' growth in a mouse xenograft model.
In search for new dimer complexes, the [Cl(NՈN’)Cu(μCl)2Cu(NՈN’)Cl] neutral water-soluble dimer complex composed from CuCl2 (normal and bridge chloride) and asymmetry NՈN’ N1,N1-dimethylethane-1,2-diamine ligand was made available. The two structural Cu(μCl2)Cu bridges formation was proved via XRD-diffraction and spectrally, moreover, the complex formula was proved by FAB-MS and elemental analysis, EDX and SEM. The [Cl(NՈN’)Cu(μCl)2Cu(NՈN’)Cl] was isolated as pure trans-Cl2-trans-(N'N’)2 structural isomer and no other isomer were detected. Each Cu(II) center exhibited five-coordinated bonds, two via N-of the asymmetric diamine ligand, one by Cl and the 2μ-Cl to form a very stable kinetic trans-trans isomer, additionally, the lattice of the crystal displayed two polar phases of CMeH–Cl and N-H….Cl long and short hydrogen bonds interactions. The Molecular Electrostatic Potential (MEP) and Hirshfeld surface theoretical dissection (HSA) supported the XRD results in detecting of the [H...Cl] short and long inter H-bonds in the lattice of the dimer. The B3LYP /DFT-IR and optimized structural parameters were matched to their experimental relatives. Moreover, TG/DTG and DSC investigated the thermal behavior of the dimer.
Copper-based antitumor drug entities 1-3 derived from substituted (F-, Br-, -CH3) 3-formylchromone pharmacophore were synthesized and thoroughly characterized by spectroscopic and single X-ray crystallographic studies. These complexes show structural novelty due to presence of the X-bonds in chromone scaffold which could facilitate higher propensity for nucleic acids via sigma σ-hole interactions. Therefore, structure-activity relationship of 1-3 was studied by performing ct-DNA binding, pBR322 cleavage and cytotoxicity activity to validate their potential to act as chemotherapeutic drug entities. The binding studies of 1-3 with ct- DNA were carried out employing many biophysical techniques and the corroborative results of these experiments showed intercalation mode of binding and the order of binding was found to be 2 > 1 >3. The structure of drug entities could facilitated strong halogen bonding interaction(in case of 1 &2) and stability of X bond was rationalized by sigma hole region of positive electrostatic potential on the surface of C-X covalent bond, as determined by gas phase B3LYP computational DFT studies. Interestingly, 2 exhibited most avid binding affinity due to presence of Br- electron withdrawing and polarizable group. Further, cleavage studies of 1-3 with pBR322 plasmid DNA were performed which demonstrated significant cleavage activity , the supercoiled form (Form I) of plasmid DNA was converted to nicked form (Form II) with the appearance of linearized form(Form III) in between two, implicating lethal double strand breaks of DNA. 2 showed predominantly higher cleavage activity following the similar trend as observed for binding studies. The cytotoxicity of the complexes 1-3 was evaluated by MTT assay against the human liver carcinoma (Huh-7) and prostate cancer (DU-145) cell lines; complex 2 exhibited specific and selective cytotoxicity for the DU-145 cancer cell line with LC50 value of 1.6μM.
Background/aims:
Hepatocellular carcinoma (HCC) is a primary malignancy of the liver and a global health problem. It is often diagnosed at advanced stage where hopeless for effective therapies. Identification of more reliable biomarkers for early detection of HCC is urgently needed. HCC is identified with hyper-vascularity feature. Herein, we sought to develop a novel score based on the combination of the most significant angiogenic biomarkers with and routine laboratory tests for accurate detection of HCC.
Material & methods:
Angiopoietin II, copper, nitric oxide, albumin, platelets count and α-fetoprotein were assayed in HCC patients (75), liver cirrhosis patients (50) and healthy control (20). Areas under receiving operating curve (AUCs) were calculated and used for construction on novel score. A novel score named HCC-AngioScore = AFP (U/L) Albumin (g/dl) × 5.4 + Angiopoietin (ng/ml) × 0.001 + Copper (mg/dl) × (-0.004) + Platelets count (×109)/L × 0.003 + Nitric oxide (μ mol/L) × 0.27-36 was developed. HCC-AngioScore produce AUC of 0.919for differentiate patients with HCC from those with liver cirrhosis with sensitivity and specificity of a cut-off 0 (i.e., less than 0 the case is considered cirrhotic, whereas above 0 it is considered HCC.
Conclusion:
HCC-AngioScore could replace AFP during screening of HCV patients and early detection of HCC.
Tetrathiomolybdate (TM) is a potent nontoxic orally delivered copper complexing agent under development for the last several years for the treatment of Wilson's disease. It has been shown to block angiogenesis in primary and metastatic tumors. Therefore, the combination of cytotoxic radiotherapy (RT) and antiangiogenic TM could target both the existing tumor and the tumor microvasculature in a comprehensive strategy. Using a Lewis lung high metastatic (LLHM) carcinoma mouse tumor model, we demonstrate that the combination of TM and RT is more effective than either used as monotherapy. We also show that their therapeutic effects are additive, with no additional toxicity. We show that TM has no significant cytotoxicity in vitro against LLHM tumor cells, further supporting the antiangiogenic mechanism for its action.
Microvascular proliferation, a hallmark of malignant brain tumors, represents an attractive target of anticancer research, especially because of the quiescent nonproliferative endothelium of the normal brain. Cerebral neoplasms sequester copper, a trace metal that modulates angiogenesis. Using a rabbit brain tumor model, normocupremic animals developed large vascularized VX2 carcinomas. By contrast, small, circumscribed, relatively avascular tumors were found in the brains of rabbits copper-depleted by diet and penicillamine treatment (CDPT). The CDPT rabbits showed a significant decrease in serum copper, copper staining of tumor cell nuclei, microvascular density, the tumor volume, endothelial cell turnover, and an increase in the vascular permeability (breakdown of the blood-brain barrier), as well as peritumoral brain edema. In non-tumor-bearing animals, CDPT did not alter the vascular permeability or the brain water content. CDPT also inhibited the intracerebral growth of the 9L gliosarcoma in F-344 rats, with a similar increase of the peritumoral vascular permeability and the brain water content. CDPT failed to inhibit tumor growth and the vascularization of the VX2 carcinoma in the thigh muscle or the metastases to the lung, findings that may reflect regional differences in the responsiveness of the endothelium, the distribution of copper, or the activity of cuproenzymes. Metabolic and pharmacologic withdrawal of copper suppresses intracerebral tumor angiogenesis; angiosuppression is a novel biologic response modifier for the in situ control of tumor growth in the brain.
Signs of copper depletion were produced in a healthy man by an amount of dietary copper (0.83 mg/day) similar to that in some contemporary diets. Urinary and fecal loss of copper exceeded intake. Plasma copper, ceruloplasmin, and superoxide dismutase activity in erythrocytes decreased. Cholesterol in plasma increased, and hematologic indices were unchanged. Lipid metabolism may be a more sensitive index of copper nutriture than are changes in hematology. The findings support the hypothesis that inadequate copper nutriture or altered copper metabolism contributes to the occurrence of ischemic heart disease.
Preclinical and in vitro studies have determined that copper is an important cofactor for angiogenesis. Tetrathiomolybdate (TM) was developed as an effective anticopper therapy for the initial treatment of Wilson's disease, an autosomal recessive disorder that leads to abnormal copper accumulation. Given the potency and uniqueness of the anticopper action of TM and its lack of toxicity, we hypothesized that TM would be a suitable agent to achieve and maintain mild copper deficiency to impair neovascularization in metastatic solid tumors. Following preclinical work that showed efficacy for this anticopper approach in mouse tumor models, we carried out a Phase I clinical trial in 18 patients with metastatic cancer who were enrolled at three dose levels of oral TM (90, 105, and 120 mg/day) administered in six divided doses with and in-between meals. Serum ceruloplasmin (Cp) was used as a surrogate marker for total body copper. Because anemia is the first clinical sign of copper deficiency, the goal of the study was to reduce Cp to 20% of baseline value without reducing hematocrit below 80% of baseline. Cp is a reliable and sensitive measure of copper status, and TM was nontoxic when Cp was reduced to 15-20% of baseline. The level III dose of TM (120 mg/ day) was effective in reaching the target Cp without added toxicity. TM-induced mild copper deficiency achieved stable disease in five of six patients who were copper deficient at the target range for at least 90 days.
The inhibition of growth is a cardinal symptom of zinc deficiency. In animals fed a zinc-inadequate diet, both food intake and growth are reduced within 4–5 d. Despite the concomitant reduction in food intake and growth, reduced energy intake is not the limiting factor in growth, because force-feeding a zinc-inadequate diet to animals fails to maintain growth. Hence, food intake and growth appear to be regulated by zinc through independent, although well coordinated, mechanisms. Despite the long-term study of zinc metabolism, the first limiting role of zinc in cell proliferation remains undefined. Zinc participates in the regulation of cell proliferation in several ways; it is essential to enzyme systems that influence cell division and proliferation. Removing zinc from the extracellular milieu results in decreased activity of deoxythymidine kinase and reduced levels of adenosine(5′)tetraphosphate(5′)-adenosine. Hence, zinc may directly regulate DNA synthesis through these systems. Zinc also influences hormonal regulation of cell division. Specifically, the pituitary growth hormone (GH)–insulin-like growth factor-I (IGF-I) axis is responsive to zinc status. Both increased and decreased circulating concentrations of GH have been observed in zinc deficiency, although circulating IGF-I concentrations are consistently decreased. However, growth failure is not reversed by maintaining either GH or IGF-I levels through exogenous administration, which suggests the defect occurs in hormone signaling. Zinc appears to be essential for IGF-I induction of cell proliferation; the site of regulation is postreceptor binding. Overall, the evidence suggests that reduced zinc availability affects membrane signaling systems and intracellular second messengers that coordinate cell proliferation in response to IGF-I.
The hypothesis that tumors are angiogenesis dependent has, in the past decade, generated new investigations designed to elucidate the mechanism of angiogenesis itself. Many laboratories are now engaged in this pursuit. Some are studying angiogenesis that occurs in physiological situations, whereas others are interested in angiogenesis that dominates pathological conditions. These efforts have led to (1) the development of bioassays for angiogenesis; (2) the partial purification and, in one case, the complete purification of angiogenic factors from neoplastic and non-neoplastic cells; (3) the development of new polymer technology for the sustained release of these factors and other macromolecules in vivo; (4) the cloning and long-term culture of capillary endothelial cells; (5) the demonstration of the role of nonendothelial cells, such as mast cells in modulating angiogenesis; (6) the discovery of angiogenesis inhibitors; and (7) the demonstration that certain animal tumors will regress when angiogenesis is inhibited. The effects of angiogenesis inhibitors provide perhaps the most compelling evidence for the role of angiogenesis in tumor growth. It is conceivable that the original effort to understand the role of angiogenesis in tumor growth will also lead to the use of angiogenesis inhibitors as a new class of pharmacologic agents in a variety of non-neoplastic diseases such as arthritis, psoriasis, and ocular neovascularization. However, much work remains to be done before it will be possible to understand (1) the regulatory systems that govern capillary density in normal tissues; (2) the factors that maintain the viability of microvascular endothelium; (3) the development of the vascular system itself; and (4) the mechanism by which vascular regression occurs, both in the embryo and in the postnatal organism. A knowledge of the mechanisms which underlie these normal processes may help to enlarge our comprehension of tumor angiogenesis.
The therapeutic actions of captopril are facilitated by its sulfhydryl moiety which interacts with the metal (Zn2+) prosthetic groups of angiotensin-converting enzyme (ACE; EC 3.4.15.1). This study focused on captopril as an inhibitor of another metal-dependent (Cu2+) enzyme, peptidylglycine-α-hydroxylating monooxygenase (PHM; EC 1.14.17.3). PHM is rate limiting in α-amidation, a COOH-terminal modification that bioactivates several pressor peptides. Captopril inhibited PHM in vitro in a dose-dependent manner with an IC50 of approximately 100 μmol/l. This inhibition was partially reversed by increased concentrations of Cu2+. Structurally similar nonsulfhydryl ACE inhibitors did not affect the activity of PHM. The present findings indicate that the therapeutic effectiveness of captopril may result from actions on a range of metalloenzymes including ACE and PHM.
Serum copper, zinc, and the Cu/Zn ratio were measured in 55 patients with breast disease (20 with benign breast diseases and 35 patients with breast cancer) and 30 controls. The mean serum copper levels were higher in breast cancer than in benign breast diseases (167.3 μg/dl) vs. 117.6 μg/dl) (P<).001) and controls (167.3 μg/dl vs. 98.8 μg/dl) (P<0.001). Patients with advanced breast cancer had higher serum copper levels than did patients with early breast cancer (177.9 μg/dl vs. 130.4 μg/dl) (P <0.001). The mean serum zinc levels were lowered only in patients with advanced breast cancer as compared with controls (88.6 μg/dl vs. 115.1 μg/dl) (P < 0.001). Serum zinc levels were not decreased in patients with early breast cancer and benign breast diseases. The Cu/Zn ratio was increased in breast cancer patients (1.91 vs. 0.86) (P < 0.001) but not in patients with benign breast diseases. The precise mechanisms responsible for the alterations in trace element levels in breast cancer patients are still unclear and require further evaluation. However, the serum copper levels and the Cu/Zn ratio may be used as biochemical markers in these patients.
Serum zinc (Zn), copper (Cu), and the Cu/Zn ratio were evaluated in 84 patients with pulmonary lesions before surgery and in 100 healthy normal controls. There were 20 patients with benign and 64 with malignant lung tumors. Only the mean (± SD) Cu/Zn ratio was significantly higher in malignant tumors (2.24 ± 0.78) than in benign tissue (1.63 ± 033) (P < 0.001). In the normal group, the Cu/Zn ratio was significantly lower (1.43 ± 0.29). Patients with advanced disease (Stage III) had higher Cu/Zn ratio than patients in Stages I and II (2.65 ± 0.86 versus 1.9 ± 0.27) (P < 0.001). At a cutoff value of 1.72, Cu/Zn ratio had a sensitivity of 89%, specificity of 84%, positive predictive value of 78%, and negative predictive value of 92% between controls and lung cancer patients. Between lung cancer patients and patients with benign pulmonary lesions the aforementioned values were 89%, 70%, 90%, and 70% respectively. A correlation between increasing Cu/Zn ratio and tumor extension and postoperative survival was observed. These findings suggest that Cu/Zn ratio may be used as a diagnostic test in lung cancer patients.
Angiogenesis is required for tumor growth and is a likely Achilles heel for cancer. However, antiangiogenic agents have been somewhat disappointing in cancer therapy, perhaps because they target a single angiogenic factor, and there is much redundancy in angiogenic systems. Copper is required for high levels of angiogenesis, and many angiogenic factors have a requirement for copper. Thus, anticopper drugs offer the possibility of more global inhibition. Our group has developed tetrathiomolybdate (TM) for the initial treatment of neurologic Wilson's disease. Penicillamine makes about 50% of these patients neurologically worse, and many never recover. Only 2 of 55 (3.6%) patients worsened when treated with TM. Because TM exhibited desirable properties of potency, speed, and safety, we studied it as an antiangiogenic agent. We hypothesize that if copper is lowered to midrange, the cellular requirements for copper are met, but angiogenic cytokine signaling is inhibited. TM has shown strong inhibition of cancer growth in five rodent models, encouraging results in a canine study of advanced and metastatic cancer, and encouraging results in a phase 1/2 study of advanced and metastatic cancer in 42 patients. Finally, we have hypothesized that the pathway of fibrosis involving transforming growth factor beta (TGF-β) and connective tissue growth factor is inhibitable by copper-lowering therapy with TM. This pathway is overactive and dysregulated in many diseases of fibrosis. In animal studies, TM has completely inhibited the pulmonary fibrosis induced by bleomycin, the hepatitis induced by concanavalin A, and the cirrhosis induced by carbon tetrachloride. We find that TM inhibits transforming growth factor beta and inflammatory cytokines tumor necrosis factor alpha and interleukin-1-beta. J. Trace Elem. Exp. Med. 16:191–199, 2003. © 2003 Wiley-Liss, Inc.
The principal objective of our work is to sufficiently understand the mechanism of angiogenesis in the adult organism to allow interference with the process on a rational basis. It is apparent that several "factors" can trigger angiogenesis. To test these, we used the rabbit cornea mostly because it is avascular (i.e., the background is zero) and transparent (i.e., the newly formed capillaries that invade the cornea are easily visible in the unanaesthetized animal). Under these conditions, it was found that the cornea ready to be colonized by capillaries under the action of an angiogenesis effector becomes rich in copper ions and sialic acid. Motility of bovine capillary endothelium was utilized to analyze the angiogenesis process on the ground that mobilization of capillary endothelium is the first morphological event observed during angiogenesis in vivo and the methods to measure cell motility are reasonably accurate. With this approach it was found that heparin, fibronectin, and gangliosides are involved in the mobilization of capillary endothelium. The precise interaction among these three components is not yet clear.
The purpose of this study was to determine the copper deposition and localization during the evolution of two murine mammary adenocarcinomas. In the normal tissue, the copper was located within the cytoplasm, whereas it was intra- and perinuclear in the tumors. The more angiogenic and metastatic tumor showed the higher percentage of copper-positive cells. In the tumor, copper deposits correlated well with its angiogenic and metastatic ability, but additional factors would be required for the process to be induced.
A nested, matched case-control study was conducted to assess the relationship between serum levels of copper and the subsequent risk of cancer. One hundred thirty-three cases of cancer were identified during 1974-1984 among 5000 members of a northwest Washington State employee cohort from whom serum specimens had been previously obtained and stored. Two hundred forty-one controls were selected at random from the cohort and were matched to the cases on the basis of age, sex, race, and date of blood draw. Serum copper levels were measured by atomic absorption spectrometry. Risk of a subsequent diagnosis of cancer was positively associated with serum copper levels, but only among those cases diagnosed within 4 years of the time the serum specimens were collected. Among cases diagnosed more than 4 years after specimen collection, there was no consistent association between serum copper levels and risk. Adjustment for age, sex, race, occupational status, cigarette smoking, family history of cancer, alcohol consumption, and, among females, use of exogenous hormones had no appreciable effect on these relationships. The findings suggest that the presence of cancer may increase serum copper levels several years prior to its diagnosis. They are less supportive of the hypothesis that serum copper levels affect cancer risk.
Serum zinc (Zn), copper (Cu), and the Cu/Zn ratio were evaluated in 84 patients with pulmonary lesions before surgery and in 100 healthy normal controls. There were 20 patients with benign and 64 with malignant lung tumors. Only the mean (+/- SD) Cu/Zn ratio was significantly higher in malignant tumors (2.24 +/- 0.78) than in benign tissue (1.63 +/- 0.33) (P less than 0.001). In the normal group, the Cu/Zn ratio was significantly lower (1.43 +/- 0.29). Patients with advanced disease (Stage III) had higher Cu/Zn ratio than patients in Stages I and II (2.65 +/- 0.86 versus 1.9 +/- 0.27) (P less than 0.001). At a cutoff value of 1.72, Cu/Zn ratio had a sensitivity of 89%, specificity of 84%, positive predictive value of 78%, and negative predictive value of 92% between controls and lung cancer patients. Between lung cancer patients and patients with benign pulmonary lesions the aforementioned values were 89%, 70%, 90%, and 70% respectively. A correlation between increasing Cu/Zn ratio and tumor extension and postoperative survival was observed. These findings suggest that Cu/Zn ratio may be used as a diagnostic test in lung cancer patients.
Recent studies have suggested that the inhibition of lymphocyte mitogenesis by D-penicillamine in the presence of copper could be mediated by the formation and action of hydrogen peroxide. To explore this possibility further, we first sought evidence of H2O2 generation by D-penicillamine in a cell-free system by a) measurement of copper-catalyzed D-penicillamine oxidation and the requirement for oxygen in this process; b) direct measurement of H2O2 formation during D-penicillamine oxidation by the peroxidase-mediated oxidation of fluorescent scopoletin; and c) evaluation of the possible synthesis of O2- during D-penicillamine oxidation. The addition of copper to D-penicillamine in physiologic buffer catalyzed D-penicillamine oxidation in a dose-dependent fashion. D-penicillamine oxidation was accompanied by O2 consumption with a molar ratio of approximately 2:1, but did not occur under anaerobic conditions. Furthermore, D-penicillamine oxidation resulted in the formation of amounts of H2O2 stoichiometrically equivalent to oxygen consumption (i.e., 1:1). Copper-catalyzed D-penicillamine oxidation caused reduction of nitroblue tetrazolium in a reaction blocked by superoxide dismutase, suggesting the formation of O2-. Additional studies confirmed that D-penicillamine inhibited PHA-induced mitogenesis of lymphocytes in the presence of copper, and that catalase protected the cells from this action. Furthermore, when polymorphonuclear leukocytes were incubated with D-penicillamine plus copper, hexose monophosphate shunt activity increased up to threefold with abrogation of this stimulation by catalase. None of the effects of D-penicillamine plus copper on cells were diminished by hydroxyl radical scavengers mannitol or benzoate. These results are consistent with oxygen-dependent copper-catalyzed oxidation of D-penicillamine in aqueous solutions leading to the formation of O2- and H2O2. H2O2 produced by this reaction can inhibit lymphocyte mitogenesis and stimulate neutrophil hexose monophosphate shunt activity in vitro and may be relevant to the therapeutic effects of D-penicillamine in vivo.
64Cu was injected in the form of CuCl2 either by subcutaneous or by intraperitoneal route, and its distribution inside different organs was analyzed in 5 different tumor models, 4 in mice and 1 in rats. In all organs tested (blood, liver, kidneys, spleen, intestine, muscle, and tumor) no significant differences were observed in the results obtained after either injection route. All tumors analyzed (Krebs ascite, intestinal Leiomyo sarcoma, human tumor, mammary adenocarcinoma, either spontaneous or chemically induced) contained a relatively high concentration of 64Cu. For all tumor models tested, the 64Cu distribution was altered as compared with that of the corresponding control animals.
This article has no abstract; the first 100 words appear below.
THE growth of solid neoplasms is always accompanied by neovascularization. This new capillary growth is even more vigorous and continuous than a similar outgrowth of capillary sprouts observed in fresh wounds or in inflammation.¹ Many workers have described the association between growing solid malignant tumors and new vessel growth.²³⁴⁵⁶ However, it has not been appreciated until the past few years that the population of tumor cells and the population of capillary endothelial cells within a neoplasm may constitute a highly integrated ecosystem. In this ecosystem the mitotic index of the two cell populations may depend upon each other. Tumor cells . . .
Supported by a grant (5 RO1 CA08185–06) from the National Cancer Institute, a grant from the American Cancer Society, National Chapter (IC-28), and gifts from the Merck Company and the Alza Corporation.
Source Information
From the Department of Surgery, Children's Hospital Medical Center and Harvard Medical School, Boston, Massachusetts 02115.
The interstitial fluid of MTW9A and Walker carcinomas and their ethanol extract induced strong angiogenic response in the rabbit (New Zealand White) corneal test. The fluid collected in vivo was rich in E-type prostaglandins, and prostaglandin E1 (PGE1) in particular was strongly angiogenic at the lowest dose as compared with the angiogenic responses of prostaglandins E2, I2, and F2 alpha. Neoplastic fibroblasts also induced a strong angiogenic response, but in indomethacin-treated rabbits neovascularization failed to occur. Copper was concentrated in the cornea during PGE1-induced neovascularization, and copper-deficient rabbits were unable to mount an angiogenic response in the corneal test. Ceruloplasmin, the copper carrier of plasma, was found to be angiogenic at high doses. In indomethacin-treated rabbits, however, ceruloplasmin at the same high doses failed to induce angiogenesis. The experiments are interpreted to indicate that angiogenesis is the end result of a sequence of events, two of which are PGE1 production and copper mobilization in the tissue where neovascularization occurs.
The ability to induce new formation of capillaries in the cornea was tested for ceruloplasmin, the copper carrier of serum, for fragments of the ceruloplasmin molecule with and without copper, for heparin, and for glycyl-L-histidyl-L-lysine, bound or not bound to copper ions. Male or female 2- to 3-kg New Zealand White rabbits were used. These experiments were prompted by the previous observation of copper accumulation in the cornea during angiogenesis and by the inability of copper-deficient rabbits to mount an angiogenic response. The results showed that the three different molecules were all able to induce angiogenesis provided that they were bound to copper. Fragments of the ceruloplasmin molecule also induced angiogenesis but only when copper was bound to the peptides. The data are interpreted to indicate that copper ions are involved in the sequence of events leading to angiogenesis and that the carrier molecules may be of quite a different nature.
Serum copper and ceruloplasmin levels are known to increase in several malignancies such as osteosarcomas, some gastrointestinal tumors, and lung cancer. In this study serum copper and ceruloplasmin levels in 40 patients with primary brain tumors were studied. Both parameters were increased in sera of patients with tumors in comparison with healthy subjects or patients with non-tumorous neurological diseases. It is concluded that copper and ceruloplasmin represent a good complement to some other nonspecific parameters in evaluating the activity of malignancy and the therapeutic results.
To investigate the effects of copper (Cu)-depletion diet and D-penicillamine treatment (CDPT) on both tumor growth and angiogenesis, we studied Fischer-344 rats in which 9L gliosarcoma cells had been subcutaneously implanted. We focused primarily on the alteration of Cu contents and the vascular density. Compared with the normal diet group, the CDPT group showed a significant reduction of tumor weight and a decrease in Cu concentration. Furthermore, the CDPT group demonstrated smaller blood vessels with significantly lower vascular density. This decrease of tumor growth was achieved by angiosuppression. Our study indicated that CDPT selectively caused Cu chelation from the tumor tissue; the normal brain tissue did not show lower Cu concentration after the treatment. The prevention of tumor angiogenesis by this method may be very useful in cancer therapy and may help elucidate the microenvironmental mechanisms for cancer cells.
Recent discoveries of endogenous negative regulators of angiogenesis, thrombospondin, angiostatin and glioma-derived angiogenesis inhibitory factor, all associated with neovascularized tumours, suggest a new paradigm of tumorigenesis. It is now helpful to think of the switch to the angiogenic phenotype as a net balance of positive and negative regulators of blood vessel growth. The extent to which the negative regulators are decreased during this switch may dictate whether a primary tumour grows rapidly or slowly and whether metastases grow at all.
Serum copper and zinc concentrations and copper/zinc ratios have been shown to be increased in several types of human malignancies, including human brain tumors. In this study, copper and zinc levels and copper/zinc ratios were determined by atomic absorption analysis in tissue and serum from 29 primary and metastatic brain tumor patients. Metastatic carcinomas and malignant gliomas revealed significantly higher tissue copper concentrations than control tissues and meningiomas. Malignant gliomas demonstrated significantly higher tissue copper/zinc ratios. Both serum copper and copper/zinc ratio were significantly higher in the metastatic carcinoma group than control; however, serum copper levels in malignant glioma patients were not significantly different from control tissues. There were no differences both in the serum and the tissue concentrations of these trace elements in meningiomas and controls. These data suggested that copper, an important angiogenic factors, is accumulated within the malignant tissues of metastatic carcinoma and malignant glioma, but not meningiomas. These findings may have implications regarding angiogenesis in these tumors.
Male Wistar rats were pair-fed from weaning for 6 wk either a copper-deficient diet or a control diet containing sucrose. Hypercholesterolemia in copper-deficient animals was associated with a significantly greater plasma apolipoprotein B concentration and modifications in the lipid composition of triglyceride-rich lipoproteins containing apolipoprotein B. The proportion of triglycerides was elevated and the proportion of cholesterol was reduced in the VLDL + LDL fractions from copper-deficient rats compared with control animals. When the VLDL + LDL fractions were subjected to in vitro copper-induced oxidation, the lipoprotein fractions from copper-deficient rats were more susceptible to oxidative damage than lipoprotein fractions from control rats as indicated by the rate of diene conjugation. Hydroperoxide and thiobarbituric acid-reactive substance (TBARS) measurements performed 3 h after the induction of peroxidation were in agreement with the greater formation of conjugated dienes. Concentrations of TBARS were significantly greater in heart homogenates from copper-deficient rats compared with control rats. After exposure of tissue homogenates to iron-induced lipid peroxidation, TBARS were significantly higher in liver and heart from copper-deficient rats compared with control rats. Of particular importance is the observation that copper deficiency has a harmful effect on lipid peroxidation in the cardiovascular system.
Serum copper, zinc, and Cu/Zn ratio were measured using atomic absorption spectrophotometry in 30 patients with colorectal cancer and compared with 30 healthy control subjects. In the patients with colorectal cancer, the tissue copper and zinc levels were also measured in paired histologically normal and malignant colorectal tissue samples obtained at surgery. The mean serum copper levels were higher in patients with colorectal cancer (165.99 vs. 98.84 micrograms/dl) (P < 0.001). The mean serum zinc levels were lowered only in advanced (Dukes stages C and D) colorectal cancer compared to controls (89.94 vs. 115.08 mu/dl) (P < 0.001). However, the Cu/Zn ratio progressively increased with the advancing stage of malignancy (1.86 vs. 0.86) (P < 0.001). The cancerous colorectal tissue showed a higher concentration of both copper (2.78 vs. 1.79 micrograms/g) (P < 0.001) and zinc (27.16 vs. 18.98 micrograms/g) (P < 0.01) compared to non-cancerous colorectal tissue. The exact mechanism responsible for the alterations in trace element levels in patients with colorectal cancer is largely unclear and requires further evaluation. However, the serum copper level and the Cu/Zn ratio are of value in estimating the extent of the carcinoma as well as in determining the prognosis of these patients.
As normal cells progress to tumorigenicity, they must develop two distinct new characteristics not possessed by the normal cells from which they arise: they must become able to multiply without restraint and they must be able to create in vivo an environment where this newly acquired growth potential can be realized. Normal cells are antiangiogenic, because they secrete only low levels of inducers of angiogenesis and high levels of molecules that inhibit neovascularization. These cells develop into successful tumors that are potently angiogenic and secrete high levels of a cocktail of molecules that induce neovascularization. It is possible to halt the production and/or release of angiogenic activity by tumor cells themselves using retinoic acid and similar compounds. Endothelial cells that form the vessels that support tumor growth can be disabled in two distinct ways. Antiangiogenic agents have distinct advantages over conventional cytotoxic cancer therapies. Although the importance of angiogenesis to the growth of tumors is now well established, the mechanism by which tumor cells develop this crucial ability to attract new blood vessels is just beginning to be explored. Available data suggest that the angiogenic phenotype develops gradually as a result of many of the same genetic changes in oncogenes and tumor suppressor genes that are also responsible for the deregulation of cell growth. The inhibitors of angiogenesis offer a new and promising avenue for tumor therapy.
The effect of the administration of captopril on Zn (zinc), Cu (copper), Ca (calcium) and Mg (magnesium) concentrations in guinea pig tissues was studied. For nine weeks 2 mg captopril per kg b.w. were administered daily to adult male guinea pigs intraperitoneally. The concentrations of the studied metals were determined in several tissues. Captopril significantly decreased Zn concentration in liver, Cu concentration in liver, adrenals, jejunum, urine and hair and Mg concentrations in blood and urine. A significant increase was observed in testicular and epididymal Zn, in heart, epididymal and fecal Cu, in Mg concentration of lung, kidney, adrenals, jejunum, epididymis and hair and in Ca concentrations in brain, heart, lung, kidney, spleen and stomach. No significant changes were observed in the colon and the thigh bone concentrations of the various elements tested. In conclusion Captopril treatment can produce translocation and/or elimination of Zn, Cu, Mg and Ca ions in various tissues of guinea pigs.
Angiogenin is a potent inducer of blood-vessel formation with ribonucleolytic activity. Angiogenin binds to high affinity endothelial cell receptors and with lower affinity to extracellular matrix components. Here we report the effect of copper and zinc on these interactions. There was a 4.3-fold increase in angiogenin binding to calf pulmonary artery endothelial cells in the presence of Cu2+ in vitro. A 3.8-fold increase was observed with Zn2+, whereas Ni2+, Co2+, or Li+ had no effect. Specific angiogenin binding to the lower affinity matrix sites was increased by 2.7- and 1.9-fold in the presence of Cu2+ and Zn2+ respectively. Metal ion affinity chromatography and atomic absorption spectrometry were used to show the direct interaction of angiogenin with copper and zinc ions. Angiogenin bound 2.4 mol of copper per mole of protein. We suggest that copper, a modulator of angiogenesis in vivo, may be involved in the regulation of the biological activity of angiogenin.
The pursuit of the ideal tumor marker has generated many tests for use in the diagnosis and management of cancer, several of which are now widely available. The objective of this study was to evaluate the diagnostic utility as a cancer marker of plasmatic levels of ceruloplasmin. Ceruloplasmin is a glucoprotein that transports serum copper. A case-control design was used. Serum values were evaluated in 144 patients and 103 normal controls by receiver operating characteristic (ROC) curve analysis to define the optimal cut-off levels for the serum values of ceruloplasmin in the diagnosis of cancer. The ROC analysis showed that ceruloplasmin is considerably sensitive in men (80%) at the specificity level of 80.3% and in women the sensitivity (Se) was (63.2%) and the specificity (Sp) was (63.3%). According to this study, it would seem optimal to use the cut-off level of 358 mg/l in men and 383 mg/l in women. In conclusion, serum ceruloplasmin was significantly elevated in advanced stages of solid malignant tumors, however, locally advanced or locoregionally spreading tumors did lead to significant increases (P < 0.01). Finally, the results of ROC curve analysis suggest that the ceruloplasmin is characteristic of good diagnostic markers.
The immune system requires copper to perform several functions, of which little is known about the direct mechanism of action. Animal models and cells in culture have been used to assess copper's role in the immune response. Some of the recent research showed that interleukin 2 is reduced in copper deficiency and is likely the mechanism by which T cell proliferation is reduced. These results were extended to show that even in marginal deficiency, when common indexes of copper are not affected by the diet, the proliferative response and interleukin concentrations are reduced. The number of neutrophils in human peripheral blood is reduced in cases of severe copper deficiency. Not only are they reduced in number, but their ability to generate superoxide anion and kill ingested microorganisms is also reduced in both overt and marginal copper deficiency. This mechanism is not yet understood. Neutrophil-like HL-60 cells accumulate copper as they differentiate into a more mature cell population and this accumulation is not reflected by increases in Cu/Zn superoxide dismutase or cytochrome-c oxidase activities. The identity of copper-binding proteins in this cell type may be useful in learning new functions of copper or assessing copper status. Neutrophils, because they are short-lived and homogeneous cell populations, are predicted to be an effective and valuable tool for assessing nutrient status in human populations.
A series of reports in the 1960s highlighted nutritional copper deficiencies in infants and children recovering from malnutrition in Peru; since that time, a cascade of additional cases in premature infants, in patients receiving total parenteral nutrition, and in those receiving special diets or unmodified cow milk have been reported. The identification by Danks that Menkes syndrome, a genetically determined defect in copper absorption and utilization, is responsible for the observed clinical manifestations provided further insight into the physiopathologic effects of copper deficiency. New information on the metabolism and physiologic role of copper, plus the identification of additional copper metalloenzymes and improvement in how to determine copper status, has fueled interpretation and speculation on how and why the classic signs of copper deficiency occur, as well as on the possible effects of mild deficiencies. Also under scrutiny are potential interactions between other elements and the effects of other elements, even when given in acceptable amounts, on copper status. There should be no constraints in thinking on other possible effects of impaired copper status in humans. I review some of the history of nutritional copper deficiency in infants and children and attempt to interpret some of the clinical manifestations in light of newly acquired information.
The interactions between tumor cells and cellular compartments of direct environment, including soluble ECM factors, in the mechanisms of cancer progressive growth are discussed. Experimental data showing the role of increased apoptotic index even with unchanged proliferation rate in achieving the tumor "dormant state" are presented. The role of various molecules and factors involved in the process of tumor angiogenesis and their value as diagnostic and prognostic markers in cancer patients is discussed. The new antitumor therapeutical strategies based on an antiangiogenic activity of new potential agents are reviewed.
Aberrant crypt foci (ACF) are preneoplastic lesions for colon cancer. Altered amounts of copper-zinc (CuZnSOD) and manganese (MnSOD) superoxide dismutases have been implicated in multistage carcinogesis of both rodents and humans. Dietary factors are potential modulators of both CuZnSOD and MnSOD activity. The purpose of this study was to investigate the interactive effects of dietary copper, manganese, and iron on 3,2'-dimethyl-4-aminobiphenyl (DMABP)-induced ACF and superoxide dismutase activities in weanling rats fed low or adequate copper (0.8 or 5.1 microg Cu/g diet), low or adequate manganese (0.6 or 17 microg Mn/g diet), and adequate or high iron (37 or 140 microg Fe/g diet). Twelve rats were allowed free access to each of these eight diets for 3.5 wk prior to DMABP administration and for an additional 8 wk after the first DMABP injection. Rats fed low dietary copper had 105% (P < 0.0001) higher formation of DMABP-induced ACF than those fed adequate dietary copper. Rats ingesting low rather than adequate dietary manganese had 23% higher formation of ACF, and rats ingesting high rather than adequate dietary iron had 18% higher formation of ACF. Heart total superoxide dismutase activity was significantly correlated with the number of ACF (r = -0.43, P < 0.0001) in rats administered DMABP. These results suggest that dietary alterations that affect superoxide dismutase activity may affect cancer susceptibility.
The cellular uptake and intracellular distribution of the essential but highly toxic nutrient, copper, is a precisely orchestrated process. Copper homeostasis is coordinated by several proteins to ensure that it is delivered to specific subcellular compartments and copper-requiring proteins without releasing free copper ions that will cause damage to cellular components. Genetic studies in prokaryotic organisms and yeast have identified membrane-associated proteins that mediate the uptake or export of copper from cells. Within cells, small cytosolic proteins, called copper chaperones, have been identified that bind copper ions and deliver them to specific compartments and copper-requiring proteins. The identification of mammalian homologues of these proteins reveal a remarkable structural and functional conservation of copper metabolism between bacteria, yeast and humans. Furthermore, studies on the function and localization of the products of the Menkes and Wilson's disease genes, which are defective in patients afflicted with these diseases, have provided valuable insight into the mechanisms of copper balance and their role in maintaining appropriate copper distribution in mammals.
Normal human prostate accumulates the highest levels of zinc of any soft tissue in the body. In contrast, the zinc level in prostate cancer is markedly decreased from the level detected in nonprostate tissues. Despite these relationships, the possible role of zinc in the growth of normal and malignant prostate has not been determined.
Growth inhibition and various regulatory responses were investigated in two human prostate carcinoma cell lines (LNCaP and PC-3), treated with or without zinc.
Incubation of the prostate carcinoma cell lines with physiological levels of zinc resulted in the marked inhibition of cell growth. A lower 50% inhibition of cell growth (IC50) value for zinc (about 100 ng/ml) was detected in LNCaP cells, which are androgen-responsive, whereas androgen-independent PC-3 cells exhibited a higher IC50 for zinc (about 700 ng/ml). Incubation with 1 microg/ml zinc resulted in maximum inhibition of growth in both cell lines. These inhibitory effects of zinc correlated well with the accumulation of zinc in the cells. Simultaneously, cell flow cytometric analyses revealed a dramatic increase of the cell population in G2/M phase, in both LNCaP (2.3-fold vs. control) and PC-3 (1.9-fold vs. control), and a decreased proportion of cells in S phase (LNCaP, -51.4%; PC-3, -23%), indicating a G2/M phase arrest. The cell growth inhibition and G2/M arrest in these cells were accompanied by an increase in apoptosis, as demonstrated by the characteristic cell morphology and further confirmed by cellular DNA fragmentation. The specificity of zinc-induced apoptosis was identified by ethylenediamine-tetraacetic acid (EDTA)-chelation, which abolished the zinc effect on cellular DNA fragmentation. The zinc-induced G2/M phase arrest and apoptosis were accompanied by increased mRNA levels of p21(Waf1/Cip1/Sdi1) in both LNCaP (p53+/+) and PC-3 (p53-/-) cells.
These results suggest that zinc inhibits human prostatic carcinoma cell growth, possibly due to induction of cell cycle arrest and apoptosis. There now exists strong evidence that the loss of a unique capability to retain high levels of zinc is an important factor in the development and progression of malignant prostate cells.
Angiogenesis, the development of a new blood supply, is an essential process of tumour growth and metastasis. Over the past few years, this has led to the consideration of the tumour vasculature as an optimal target for anti-cancer strategies. The process of angiogenesis consists of a series of interactive events: quiescent endothelial cells are stimulated by angiogenic factors to degrade the underlying basement membrane, to migrate within the interstitial matrix, to proliferate and to organise themselves into tubular structures which become mature blood vessels. During angiogenesis, the endothelial cells undergo functional changes and show molecular features which are different from normal, quiescent endothelium. These differences can be exploited in order to selectively target tumour endothelium and to prevent neo-vessel formation. Two main approaches have been followed: i. the inhibition of the angiogenic process and vessel formation (anti-angiogenesis), and ii. direct targeting and destruction of tumour vasculature (vascular targeting). Compounds of different origin and mechanism of action have the potential to inhibit angiogenesis and hence tumour growth. This review takes into consideration some angiogenesis antagonists that are in development and the leader compounds that are under clinical trial for the treatment of cancer.
We wish to thank Terry Schoop of Biomed Arts Associates, San Francisco, for preparation of the figures, Cori Bargmann and Zena Werb for insightful comments on the manuscript, and Normita Santore for editorial assistance. In addition, we are indebted to Joe Harford and Richard Klausner, who allowed us to adapt and expand their depiction of the cell signaling network, and we appreciate suggestions on signaling pathways from Randy Watnick, Brian Elenbas, Bill Lundberg, Dave Morgan, and Henry Bourne. R. A. W. is a Ludwig Foundation and American Cancer Society Professor of Biology. His work has been supported by the Department of the Army and the National Institutes of Health. D. H. acknowledges the support and encouragement of the National Cancer Institute. Editorial policy has rendered the citations illustrative but not comprehensive.