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Since most copper supplements come in pill form, consuming them is as easy as a swallow. The estimated intake levels for copper supplements are: If you add ammonia solution to a solution containing hexaaquacopper(II) ions, [Cu(H 2O) 6] 2+, four of the water molecules are eventually replaced by ammonia molecules to give [Cu(NH 3) 4(H 2O) 2] 2+. Ishida, S., Andreux, P., Poitry-Yamate, C., Auwerx, J. & Hanahan, D. Bioavailable copper modulates oxidative phosphorylation and growth of tumors. Proc. Natl Acad. Sci. USA 110, 19507–19512 (2013).
This second structure is known as a chelate from a Greek word meaning a crab's claw. You can picture the copper ion as being nipped by the claw of the 1,2-diaminoethane molecule. We previously showed that in an orthotopic model of TNBC (MDA-MB-231-LM2 or LM2), copper depletion did not impact primary tumor growth of cells, but significantly reduce lung metastases 23. LM2 cells are a lung-tropic variant of the human MDA-MB-231 cell line which were selected for an enhanced ability to metastasize to lung tissue through two rounds of in vivo selection 35. To extend these observations in a physiologically relevant, immunocompetent setting, we leveraged the syngeneic EO771 mouse model of TNBC containing homozygous mutations in Trp53 and KRAS 36. This model is weakly metastatic to the lungs, but, following a similar procedure of in vivo selection, we generated a lung tropic variant cell line EO771.ML1 (ML1), after sorting mCherry+ cells from lung nodules (Fig. 1e, top panel). We then confirmed ML1 cells labeled with mCherry and firefly luciferase aggressively metastasized to lung tissue following orthotopic injection into the mammary fat pad.Yu, M. Generation, function and diagnostic value of mitochondrial DNA copy number alterations in human cancers. Life Sci. 89, 65–71 (2011). There are a few major concerns associated with copper supplements. The first is the aforementioned risk of depleted zinc and Vitamin C levels as a result of too high copper intake. While this risk is one that can be easily managed with the right monitoring, it often requires time and effort before balance can be properly achieved. The additional cost of testing zinc and Vitamin C levels in comparison to copper is something that also needs to be accounted for. Write down expressions for all the individual values (the first two are done for you above), and then multiply those expressions together. You will find that all the terms for the intermediate ions cancel out to leave you with the expression for the overall stability constant.
The concentration of the water is approximately constant. The equilibrium constant is defined so that you avoid having an extra unnecessary constant in the expression.Covini, D. et al. Expanding targets for a metabolic therapy of cancer: l-asparaginase. Recent Pat. Anticancer Drug Discov. 7, 4–13 (2012). Canto, C. & Auwerx, J. AMP-activated protein kinase and its downstream transcriptional pathways. Cell. Mol. Life Sci. 67, 3407–3423 (2010).
To perform gene ontology (GO) analysis of downregulated proteins, we analyzed the proteomics data with relaxed stringency (log2 fold change >0.6 or <−0.6 and p< 0.05). Analysis showed enrichment of pathways involved in the mitochondrial electron transport chain (ETC), specifically in ML1 GFP+ cells following TM treatment (Fig. 2f, g). Similarly, LM2 GFP+ and GFP− cells sorted from human LM2 cell line were also analyzed for quantitative protein abundance profiling performed using LC–MS following TM treatment for 48 h, and then GO analysis on downregulated proteins (log2 fold change < −0.6 and p< 0.05), revealed similar results for preferential enrichment of pathways associated with mitochondrial ETC in GFP+ cells (Supplementary Fig. 2b, c). Thus, TM treatment specifically impacted mitochondrial ETC pathways in SOX2/OCT4+ cells with higher intracellular copper levels. Copper depletion disrupts mitochondrial respiration in TNBC cells Badet, J. et al. Specific binding of angiogenin to calf pulmonary artery endothelial cells. Proc. Natl Acad. Sci. USA 86, 8427–8431 (1989).Copper may also be used to kill cancer cells more directly. A 2019 study indicated that treatment with copper nanoparticles delayed the growth of pancreatic tumors in mice. According to research from 2015, high concentrations of copper in the blood are linked to several kinds of cancer, including breast and lung cancer. Cruz-Bermudez, A. et al. PGC-1alpha levels correlate with survival in patients with stage III NSCLC and may define a new biomarker to metabolism-targeted therapy. Sci. Rep. 7, 16661 (2017). Goodwin, P. J. et al. Effect of metformin vs placebo on and metabolic factors in NCIC CTG MA.32. J. Natl Cancer Inst. 107, djv006 https://doi.org/10.1093/jnci/djv006 (2015).
This is an ionic copper solution with high bioavailability. This means it’s extremely easy for just about everyone to digest and absorb, offering efficient and optimum results within a short period of time. 4) NutriNoche Nano Colloidal Copper LiquidExperiments contained positive and negative controls and were repeated for reproducibility and statistical rigor. Two independent TNBC models (human and murine) were used. Copper chelation was performed using two independent drugs TM (0.5 µM) and trientine (50 µM), and pharmacological findings were confirmed with precise genetic approaches. Statistical analyses were performed using an unpaired t-test with a normality test. Any outlier, if at all, was excluded after analyzing the datasets with the ROUT method. T-test was used to analyze significance between two groups. If the data did not pass the normality test, the Mann–Whitney test was used to calculate significance between two groups. One-way ANOVA with Tukey post-test was used for comparing three or more groups. For comparing metabolites, two-way ANOVA was used. p values < 0.05 were considered statistically significant. Results are expressed as mean ± SD unless otherwise mentioned. Reporting summary Malhotra, M. K. & Emens, L. A. The evolving management of metastatic triple negative breast cancer. Semin. Oncol. 47, 229–237 (2020). While there has been significant progress in understanding the contribution of metabolic reprogramming to tumor growth, the role of metabolism in facilitating metastasis is poorly understood 26. Indeed, the SOX2/OCT4+ cells with high intracellular copper exhibited elevated OXPHOS compared to SOX2/OCT4− cells, a finding consistent with the notion that tumors are metabolically heterogeneous, and that cancer stem cells with high metastatic and tumorigenic potential are more reliant upon OXPHOS than the bulk tumors 58, 59. Indeed, copper enriched SOX2/OCT4+ cells were markedly sensitive to copper depletion, as inactivation of Complex IV significantly reduced OXPHOS and increased glycolysis resulting in impaired invasion and metastatic phenotypes. Together, these findings provide the most direct evidence linking copper-induced metabolic reprograming and metastasis in TNBC. Copper is an essential cofactor for a host of metalloenzymes/proteins that contribute to carcinogenesis 10, 11, 60, 61, so it is conceivable that copper depletion is likely to elicit context-dependent effects based on tumor type and organ-specific microenvironments. Indeed, copper chelation in the RIP-Tag model of pancreatic cancer, expressing the SV40T oncogene under control of the rat insulin promoter, and in human endometrial cancer cells resulted in Complex IV inactivation and HIF-1α stabilization 56, 62 or inhibition of SOD1 63. Similarly, copper depletion was able to overcome resistance to BRAF and MEK1/2 inhibitors 17, and regulated autophagy in lung adenocarcinoma 18. Fig. 1 (A) Scheme highlighting mechanisms that can increase intracellular Cu ion levels. Exposure to external agents and mis-folded peptides can cause increased levels of reactive oxygen species (ROS) leading to oxidative stress. Increased oxidative stress leads to protein oxidation releasing Cu ions from proteins and also reduces levels of glutathione (GSH) bound Cu +. Mutations in Cu ion transporters lead to elevated intracellular Cu ion levels. (B) Cu +/Cu 2+ catalyzed Fenton reaction produces reactive hydroxyl radicals, HO˙. Cu 2+ is reduced by cellular reductants like superoxide (O 2˙ −) and hydroascorbate (AscH −) to complete the catalytic cycle. (C) Proposed cell-permeable Cu 2+ chelators that alleviate oxidative stress via selective Cu 2+ chelation.
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