Copper in colorectal cancer: From copper-related mechanisms to clinical cancer therapies

Abstract

Copper, a trace element and vital cofactor, plays a crucial role in the maintenance of biological functions. Recent evidence has established significant correlations between copper levels, cancer development and metastasis. The strong redox-active properties of copper offer both benefits and disadvantages to cancer cells. The intestinal tract, which is primarily responsible for copper uptake and regulation, may suffer from an imbalance in copper homeostasis. Colorectal cancer (CRC) is the most prevalent primary cancer of the intestinal tract and is an aggressive malignant disease with limited therapeutic options. Current research is primarily focused on the relationship between copper and CRC. Innovative concepts, such as cuproplasia and cuproptosis, are being explored to understand copper-related cellular proliferation and death. Cuproplasia is the regulation of cell proliferation that is mediated by both enzymatic and nonenzymatic copper-modulated activities. Whereas, cuproptosis refers to cell death induced by excess copper via promoting the abnormal oligomerisation of lipoylated proteins within the tricarboxylic acid cycle, as well as by diminishing the levels of iron-sulphur cluster proteins. A comprehensive understanding of copper-related cellular proliferation and death mechanisms offers new avenues for CRC treatment. In this review, we summarise the evolving molecular mechanisms, ranging from abnormal intracellular copper concentrations to the copper-related proteins that are being discovered, and discuss the role of copper in the pathogenesis, progression and potential therapies for CRC. Understanding the relationship between copper and CRC will help provide a comprehensive theoretical foundation for innovative treatment strategies in CRC management.

Keywords

cancer therapy / colorectal cancer / copper / cuproptosis

References

[1] Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17-48.

[2] Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394:1467-1480.

[3] Li J, Ma X, Chakravarti D, Shalapour S, Depinho RA. Genetic and biological hallmarks of colorectal cancer. Genes Dev. 2021;35:787-820.

[4] Festa RA, Thiele DJ. Copper: an essential metal in biology. Curr Biol. 2011;21:R877-R883.

[5] Brady DC, Crowe MS, Turski ML, et al. Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature. 2014;509:492-496.

[6] Shanbhag V, Jasmer-Mcdonald K, Zhu S, et al. ATP7A delivers copper to the lysyl oxidase family of enzymes and promotes tumorigenesis and metastasis. Proc Natl Acad Sci U S A. 2019;116:6836-6841.

[7] Tsang T, Posimo JM, Gudiel AA, Cicchini M, Feldser DM, Brady DC. Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma. Nat Cell Biol. 2020;22:412-424.

[8] Xiong C, Ling H, Hao Q, Zhou X. Cuproptosis: p53-regulated metabolic cell death? Cell Death Differ. 2023;30:876-884.

[9] Matassa DS, Amoroso MR, Lu H, Avolio R, et al. Oxidative metabolism drives inflammation-induced platinum resistance in human ovarian cancer. Cell Death Differ. 2016;23:1542-1554.

[10] Porporato PE, Filigheddu N, Pedro JMB-S, Kroemer G, Galluzzi L. Mitochondrial metabolism and cancer. Cell Res. 2018;28:265-280.

[11] Grochowski C, Blicharska E, Baj J, et al. Serum iron, magnesium, copper, and manganese levels in alcoholism: a systematic review. Molecules. 2019;24:1361.

[12] Linder Mc, Wooten L, Cerveza P, Cotton S, Shulze R, Lomeli N. Copper transport. Am J Clin Nutr. 1998;67:965S-971S.

[13] Feng Y, Zeng J-W, Ma Q, Zhang S, Tang J, Feng J-F. Serum copper and zinc levels in breast cancer: a meta-analysis. J Trace Elem Med Biol. 2020;62:126629.

[14] Wu Z, Lv G, Xing F, et al. Copper in hepatocellular carcinoma: a double-edged sword with therapeutic potentials. Cancer Lett. 2023;571:216348.

[15] Moriya M, Ho Y-H, Grana A, et al. Copper is taken up efficiently from albumin and alpha2-macroglobulin by cultured human cells by more than one mechanism. Am J Physiol Cell Physiol. 2008;295:C708-C721.

[16] Ramos D, Mar D, Ishida M, et al. Mechanism of copper uptake from blood plasma ceruloplasmin by mammalian cells. PLoS One. 2016;11:e0149516.

[17] Sharp PA. Ctr1 and its role in body copper homeostasis. Int J Biochem Cell Biol. 2003;35:288-291.

[18] Weiss KC, Linder MC. Copper transport in rats involving a new plasma protein. Am J Physiol. 1985;249:E77-E88.

[19] Klevay LM. Cardiovascular disease from copper deficiency – a history. J Nutr. 2000;130:489S-492S.

[20] Myint ZW, Oo TH, Thein KZ, Tun AM, Saeed H. Copper deficiency anemia: review article. Ann Hematol. 2018;97:1527-1534.

[21] Strain JJ. A reassessment of diet and osteoporosis–possible role for copper. Med Hypotheses. 1988;27:333-338.

[22] Tadini-Buoninsegni F, Smeazzetto S. Mechanisms of charge transfer in human copper ATPases ATP7A and ATP7B. IUBMB Life. 2017;69:218-225.

[23] Tümer Z, Møller LB. Menkes disease. Eur J Hum Genet. 2010;18:511-518.

[24] Cobine PA, Moore SA, Leary SC. Getting out what you put in: copper in mitochondria and its impacts on human disease. Biochim Biophys Acta Mol Cell Res. 2021;1868:118867.

[25] Feng J-F, Lu L, Zeng P, et al. Serum total oxidant/antioxidant status and trace element levels in breast cancer patients. Int J Clin Oncol. 2012;17:575-583.

[26] Feng W, Ye F, Xue W, Zhou Z, Kang YJ. Copper regulation of hypoxia-inducible factor-1 activity. Mol Pharmacol. 2009;75:174-182.

[27] Ge EJ, Bush AI, Casini A, et al. Connecting copper and cancer: from transition metal signalling to metalloplasia. Nat Rev Cancer. 2022;22:102-113.

[28] Ishida S, Andreux P, Poitry-Yamate C, Auwerx J, Hanahan D. Bioavailable copper modulates oxidative phosphorylation and growth of tumors. Proc Natl Acad Sci U S A. 2013;110:19507-19512.

[29] Gu M, Cooper J, Butler P, et al. Oxidative-phosphorylation defects in liver of patients with Wilson's disease. Lancet. 2000;356:469-474.

[30] Bremner I. Manifestations of copper excess. Am J Clin Nutr. 1998;67:1069S-1073S.

[31] Kawakami M, Inagawa R, Hosokawa T, Saito T, Kurasaki M. Mechanism of apoptosis induced by copper in PC12 cells. Food Chem Toxicol. 2008;46:2157-2164.

[32] Sutton HC, Winterbourn CC. On the participation of higher oxidation states of iron and copper in Fenton reactions. Free Radic Biol Med. 1989;6:53-60.

[33] Li G-N, Zhao X-J, Wang Z, et al. Elaiophylin triggers paraptosis and preferentially kills ovarian cancer drug-resistant cells by inducing MAPK hyperactivation. Signal Transduct Target Ther. 2022;7:317.

[34] Zhou Y, Huang F, Yang Y, et al. Paraptosis-Inducing nanomedicine overcomes cancer drug resistance for a potent cancer therapy. Small. 2018;14:1702446.

[35] Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060-1072.

[36] Kabolizadeh P, Ryan J, Farrell N. Differences in the cellular response and signaling pathways of cisplatin and BBR3464 ([[trans-PtCl(NH3)(2)]2mu-(trans-Pt(NH3)(2)(H2N(CH2)(6)-NH2)2)]4+) influenced by copper homeostasis. Biochem Pharmacol. 2007;73:1270-1279.

[37] Yang F, Pei R, Zhang Z, et al. Copper induces oxidative stress and apoptosis through mitochondria-mediated pathway in chicken hepatocytes. Toxicol In Vitro. 2019;54:310-316.

[38] Shen W-Y, Jia C-P, Liao L-Y, et al. Copper(II) complex enhanced chemodynamic therapy through GSH depletion and autophagy flow blockade. Dalton Trans. 2023;52:3287-3294.

[39] Galdino ACM, Viganor L, Pereira MM, et al. Copper(II) and silver(I)-1,10-phenanthroline-5,6-dione complexes interact with double-stranded DNA: further evidence of their apparent multi-modal activity towards Pseudomonas aeruginosa. J Biol Inorg Chem. 2022;27:201-213.

[40] Liu N, Liu C, Li X, et al. A novel proteasome inhibitor suppresses tumor growth via targeting both 19S proteasome deubiquitinases and 20S proteolytic peptidases. Sci Rep. 2014;4:5240.

[41] Tardito S, Bassanetti I, Bignardi C, et al. Copper binding agents acting as copper ionophores lead to caspase inhibition and paraptotic cell death in human cancer cells. J Am Chem Soc. 2011;133:6235-6242.

[42] Barilli A, Atzeri C, Bassanetti I, et al. Oxidative stress induced by copper and iron complexes with 8-hydroxyquinoline derivatives causes paraptotic death of HeLa cancer cells. Mol Pharm. 2014;11:1151-1163.

[43] Ren X, Li Y, Zhou Y, et al. Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis. Redox Biol. 2021;46:102122.

[44] Gao W, Huang Z, Duan J, Nice EC, Lin J, Huang C. Elesclomol induces copper-dependent ferroptosis in colorectal cancer cells via degradation of ATP7A. Mol Oncol. 2021;15:3527-3544.

[45] Xue Q, Yan D, Chen X, et al. Copper-dependent autophagic degradation of GPX4 drives ferroptosis. Autophagy. 2023;19:1982-1996.

[46] Li F, Wu X, Liu H, et al. Copper depletion strongly enhances ferroptosis via mitochondrial perturbation and reduction in antioxidative mechanisms. Antioxidants (Basel). 2022;11:2084.

[47] Martin F, Linden T, Katschinski DM, et al. Copper-dependent activation of hypoxia-inducible factor (HIF)-1: implications for ceruloplasmin regulation. Blood. 2005;105:4613-4619.

[48] Zhou H, Liu Z, Zhang Z, et al. Copper-cysteamine nanoparticle-mediated microwave dynamic therapy improves cancer treatment with induction of ferroptosis. Bioact Mater. 2023;24:322-330.

[49] Tsvetkov P, Coy S, Petrova B, et al. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science. 2022;375:1254-1261.

[50] Li L, Sun F, Kong F, et al. Characterization of a cuproptosis-related signature to evaluate immune features and predict prognosis in colorectal cancer. Front Oncol. 2023;13:1083956.

[51] Tsvetkov P, Detappe A, Cai K, et al. Mitochondrial metabolism promotes adaptation to proteotoxic stress. Nat Chem Biol. 2019;15:681-689.

[52] Mason KE. A conspectus of research on copper metabolism and requirements of man. J Nutr. 1979;109:1979-2066.

[53] Dancis A, Roman DG, Anderson GJ, Hinnebusch AG, Klausner RD. Ferric reductase of Saccharomyces cerevisiae: molecular characterization, role in iron uptake, and transcriptional control by iron. Proc Natl Acad Sci U S A. 1992;89:3869-3873.

[54] Georgatsou E, Mavrogiannis LA, Fragiadakis GS, Alexandraki D. The yeast Fre1p/Fre2p cupric reductases facilitate copper uptake and are regulated by the copper-modulated Mac1p activator. J Biol Chem. 1997;272:13786-13792.

[55] Lane D, Bae DH, Merlot AM, Sahni S, Richardson DR. Duodenal cytochrome b (DCYTB) in iron metabolism: an update on function and regulation. Nutrients. 2015;7:2274-2296.

[56] McKie AT, Barrow D, Latunde-Dada GO, et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science. 2001;291:1755-1759.

[57] Gomes IM, Maia CJ, Santos CR. STEAP proteins: from structure to applications in cancer therapy. Mol Cancer Res. 2012;10:573-587.

[58] Ohgami RS, Campagna DR, Greer EL, et al. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet. 2005;37:1264-1269.

[59] Finegold AA, Shatwell KP, Segal AW, Klausner RD, Dancis A. Intramembrane bis-heme motif for transmembrane electron transport conserved in a yeast iron reductase and the human NADPH oxidase. J Biol Chem. 1996;271:31021-31024.

[60] Arnesano F, Natile G. Interference between copper transport systems and platinum drugs. Semin Cancer Biol. 2021;76:173-188.

[61] Colombo E, Triolo D, Bassani C, et al. Dysregulated copper transport in multiple sclerosis may cause demyelination via astrocytes. Proc Natl Acad Sci U S A. 2021;118:e2025804118.

[62] Ilyechova E, Bonaldi E, Orlov I, Skomorokhova E, Puchkova L, Broggini M. CRISP-R/Cas9 mediated deletion of copper transport genes CTR1 and DMT1 in NSCLC cell line H1299. Biological and pharmacological consequences. Cells. 2019;8:322.

[63] Lin C, Zhang Z, Wang T, Chen C, James Kang Y. Copper uptake by DMT1: a compensatory mechanism for CTR1 deficiency in human umbilical vein endothelial cells. Metallomics. 2015;7:1285-1289.

[64] Lönnerdal B. Intestinal regulation of copper homeostasis: a developmental perspective. Am J Clin Nutr. 2008;88:846S-850S.

[65] Liang ZD, Tsai W-B, Lee M-Y, Savaraj N, Kuo MT. Specificity protein 1 (sp1) oscillation is involved in copper homeostasis maintenance by regulating human high-affinity copper transporter 1 expression. Mol Pharmacol. 2012;81:455-464.

[66] Lee J, Petris MJ, Thiele DJ. Characterization of mouse embryonic cells deficient in the ctr1 high affinity copper transporter. Identification of a Ctr1-independent copper transport system. J Biol Chem. 2002;277:40253-40259.

[67] Nose Y, Kim B-E, Thiele DJ. Ctr1 drives intestinal copper absorption and is essential for growth, iron metabolism, and neonatal cardiac function. Cell Metab. 2006;4:235-244.

[68] Öhrvik H, Nose Y, Wood LK, et al. Ctr2 regulates biogenesis of a cleaved form of mammalian Ctr1 metal transporter lacking the copper- and cisplatin-binding ecto-domain. Proc Natl Acad Sci U S A. 2013;110:E4279-E4288.

[69] Öhrvik H, Thiele DJ. The role of Ctr1 and Ctr2 in mammalian copper homeostasis and platinum-based chemotherapy. J Trace Elem Med Biol. 2015;31:178-182.

[70] Aggett PJ. An overview of the metabolism of copper. Eur J Med Res. 1999;4:214-216.

[71] Peña MMO, Lee J, Thiele DJ. A delicate balance: homeostatic control of copper uptake and distribution. J Nutr. 1999;129:1251-1260.

[72] Thiele DJ. Integrating trace element metabolism from the cell to the whole organism. J Nutr. 2003;133:1579S-1580S.

[73] La Fontaine S, Mercer JFB. Trafficking of the copper-ATPases, ATP7A and ATP7B: role in copper homeostasis. Arch Biochem Biophys. 2007;463:149-167.

[74] Lutsenko S, Barnes NL, Bartee MY, Dmitriev OY. Function and regulation of human copper-transporting ATPases. Physiol Rev. 2007;87:1011-1046.

[75] Cabrera A, Alonzo E, Sauble E, et al. Copper binding components of blood plasma and organs, and their responses to influx of large doses of (65)Cu, in the mouse. Biometals. 2008;21:525-543.

[76] Kirsipuu T, Zadorožnaja A, Smirnova J, et al. Copper(II)-binding equilibria in human blood. Sci Rep. 2020;10:5686.

[77] Jiang X, Chen J, Bajić A, et al. Quantitative real-time imaging of glutathione. Nat Commun. 2017;8:16087.

[78] Juárez-Rebollar D, Rios C, Nava-Ruíz C, Méndez-Armenta M. Metallothionein in brain disorders. Oxid Med Cell Longev. 2017;2017:5828056.

[79] Maryon EB, Molloy SA, Kaplan JH. Cellular glutathione plays a key role in copper uptake mediated by human copper transporter 1. Am J Physiol Cell Physiol. 2013;304:C768-C779.

[80] Bonaccorsi M, Knight MJ, Le Marchand T, et al. Multimodal response to copper binding in superoxide dismutase dynamics. J Am Chem Soc. 2020;142:19660-19667.

[81] Freedman JH, Ciriolo MR, Peisach J. The role of glutathione in copper metabolism and toxicity. J Biol Chem. 1989;264:5598-5605.

[82] Rae TD, Schmidt PJ, Pufahl RA, Culotta VC, O'Halloran TV. Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science. 1999;284:805-808.

[83] Gudekar N, Shanbhag V, Wang Y, Ralle M, Weisman GA, Petris MJ. Metallothioneins regulate ATP7A trafficking and control cell viability during copper deficiency and excess. Sci Rep. 2020;10:7856.

[84] Casareno RLB, Waggoner D, Gitlin JD. The copper chaperone CCS directly interacts with copper/zinc superoxide dismutase. J Biol Chem. 1998;273:23625-23628.

[85] Furukawa Y, Torres AS, O'halloran TV. Oxygen-induced maturation of SOD1: a key role for disulfide formation by the copper chaperone CCS. EMBO J. 2004;23:2872-2881.

[86] Dong X, Zhang Z, Zhao J, et al. The rational design of specific SOD1 inhibitors via copper coordination and their application in ROS signaling research. Chem Sci. 2016;7:6251-6262.

[87] Sturtz LA, Diekert K, Jensen LT, Lill R, Culotta VC. A fraction of yeast Cu,Zn-superoxide dismutase and its metallochaperone, CCS, localize to the intermembrane space of mitochondria. A physiological role for SOD1 in guarding against mitochondrial oxidative damage. J Biol Chem. 2001;276:38084-38089.

[88] Punter FA, Adams DL, Glerum DM. Characterization and localization of human COX17, a gene involved in mitochondrial copper transport. Hum Genet. 2000;107:69-74.

[89] Morgada MN, Abriata LA, Cefaro C, Gajda K, Banci L, Vila AJ. Loop recognition and copper-mediated disulfide reduction underpin metal site assembly of CuA in human cytochrome oxidase. Proc Natl Acad Sci U S A. 2015;112:11771-11776.

[90] Cobine PA, Pierrel F, Winge DR. Copper trafficking to the mitochondrion and assembly of copper metalloenzymes. Biochim Biophys Acta. 2006;1763:759-772.

[91] Timón-Gómez A, Nývltová E, Abriata LA, Vila AJ, Hosler J, Barrientos A. Mitochondrial cytochrome c oxidase biogenesis: recent developments. Semin Cell Dev Biol. 2018;76:163-178.

[92] Suzuki C, Daigo Y, Kikuchi T, Katagiri T, Nakamura Y. Identification of COX17 as a therapeutic target for non-small cell lung cancer. Cancer Res. 2003;63:7038-7041.

[93] Itoh S, Kim HW, Nakagawa O, et al. Novel role of antioxidant-1 (Atox1) as a copper-dependent transcription factor involved in cell proliferation. J Biol Chem. 2008;283:9157-9167.

[94] Hamza I, Faisst A, Prohaska J, Chen J, Gruss P, Gitlin JD. The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis. Proc Natl Acad Sci U S A. 2001;98:6848-6852.

[95] Zhang X, Walke GR, Horvath I, et al. Memo1 binds reduced copper ions, interacts with copper chaperone Atox1, and protects against copper-mediated redox activity in vitro. Proc Natl Acad Sci U S A. 2022;119:e2206905119.

[96] Fujieda N, Umakoshi K, Ochi Y, et al. Copper-oxygen dynamics in the tyrosinase mechanism. Angew Chem Int Ed Engl. 2020;59:13385-13390.

[97] Xiao T, Ackerman CM, Carroll EC, et al. Copper regulates rest-activity cycles through the locus coeruleus-norepinephrine system. Nat Chem Biol. 2018;14:655-663.

[98] Chen W, Yang A, Jia J, Popov YV, Schuppan D, You H. Lysyl oxidase (LOX) family members: rationale and their potential as therapeutic targets for liver fibrosis. Hepatology. 2020;72:729-741.

[99] Salmi M, Jalkanen S. VAP-1: an adhesin and an enzyme. Trends Immunol. 2001;22:211-216.

[100] Hwang JJ, Park M-H, Koh J-Y. Copper activates TrkB in cortical neurons in a metalloproteinase-dependent manner. J Neurosci Res. 2007;85:2160-2166.

[101] Michniewicz F, Saletta F, Rouaen JRC, et al. Copper: an intracellular achilles' heel allowing the targeting of epigenetics, kinase pathways, and cell metabolism in cancer therapeutics. ChemMedChem. 2021;16:2315-2329.

[102] He F, Chang C, Liu B, et al. Copper (II) ions activate ligand-independent receptor tyrosine kinase (RTK) signaling pathway. Biomed Res Int. 2019;2019:4158415.

[103] Turski ML, Brady DC, Kim HJ, et al. A novel role for copper in Ras/mitogen-activated protein kinase signaling. Mol Cell Biol. 2012;32:1284-1295.

[104] Opazo CM, Lotan A, Xiao Z, et al., Nutrient copper signaling promotes protein turnover by allosteric activation of ubiquitin E2D conjugases. bioRxiv. 2021.

[105] Barresi V, Trovato-Salinaro A, Spampinato G, et al. Transcriptome analysis of copper homeostasis genes reveals coordinated upregulation of SLC31A1,SCO1, and COX11 in colorectal cancer. FEBS Open Bio. 2016;6:794-806.

[106] Baszuk P, Marciniak W, Derkacz R, et al. Blood copper levels and the occurrence of colorectal cancer in Poland. Biomedicines. 2021;9:1628.

[107] Gupta SK, Shukla VK, Vaidya MP, Roy SK, Gupta S. Serum and tissue trace elements in colorectal cancer. J Surg Oncol. 1993;52:172-175.

[108] Sharma K, Mittal DK, Kesarwani RC, Kamboj VP, Chowdhery . Diagnostic and prognostic significance of serum and tissue trace elements in breast malignancy. Indian J Med Sci. 1994;48:227-232.

[109] Aubert L, Nandagopal N, Steinhart Z, et al. Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer. Nat Commun. 2020;11:3701.

[110] Polishchuk EV, Merolla A, Lichtmannegger J, et al. Activation of autophagy, observed in liver tissues from patients with wilson disease and from ATP7B-deficient animals, protects hepatocytes from copper-induced apoptosis. Gastroenterology. 2019;156:1173-1189. e1175.

[111] Liao Y, Zhao J, Bulek K, et al. Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis. Nat Commun. 2020;11:900.

[112] Gurusamy KS, Farquharson MJ, Craig C, Davidson BR. An evaluation study of trace element content in colorectal liver metastases and surrounding normal livers by X-ray fluorescence. Biometals. 2008;21:373-378.

[113] Bhuvanasundar R, John A, Sulochana K, Coral K, Deepa PR, Umashankar V. A molecular model of human Lysyl Oxidase (LOX) with optimal copper orientation in the catalytic cavity for induced fit docking studies with potential modulators. Bioinformation. 2014;10:406-412.

[114] Denoyer D, Masaldan S, La Fontaine S, Cater MA. Targeting copper in cancer therapy: ‘Copper That Cancer’. Metallomics. 2015;7:1459-1476.

[115] Jana A, Das A, Krett NL, et al. Nuclear translocation of Atox1 potentiates activin A-induced cell migration and colony formation in colon cancer. PLoS One. 2020;15:e0227916.

[116] Lowndes SA, Harris AL. The role of copper in tumour angiogenesis. J Mammary Gland Biol Neoplasia. 2005;10:299-310.

[117] Finney L, Vogt S, Fukai T, Glesne D. Copper and angiogenesis: unravelling a relationship key to cancer progression. Clin Exp Pharmacol Physiol. 2009;36:88-94.

[118] Pan Q, Kleer CG, van Golen KL, et al. Copper deficiency induced by tetrathiomolybdate suppresses tumor growth and angiogenesis. Cancer Res. 2002;62:4854-4859.

[119] Xie H, Kang Y. Role of copper in angiogenesis and its medicinal implications. Curr Med Chem. 2009;16:1304-1314.

[120] Urso E, Maffia M. Behind the link between copper and angiogenesis: established mechanisms and an overview on the role of vascular copper transport systems. J Vasc Res. 2015;52:172-196.

[121] Rigiracciolo DC, Scarpelli A, Lappano R, et al. Copper activates HIF-1alpha/GPER/VEGF signalling in cancer cells. Oncotarget. 2015;6:34158-34177.

[122] Onuma T, Mizutani T, Fujita Y, Yamada S, Yoshida Y. Copper content in ascitic fluid is associated with angiogenesis and progression in ovarian cancer. J Trace Elem Med Biol. 2021;68:126865.

[123] Das A, Ash D, Fouda AY, et al. Cysteine oxidation of copper transporter CTR1 drives VEGFR2 signalling and angiogenesis. Nat Cell Biol. 2022;24:35-50.

[124] Li Z, Li S, Wen Y, Chen J, Liu K, Jia J. MiR-495 inhibits cisplatin resistance and angiogenesis in esophageal cancer by targeting ATP7A. Technol Cancer Res Treat. 2021;20:15330338211039127.

[125] Shih Y-H, Chang K-W, Chen MY, et al. Lysyl oxidase and enhancement of cell proliferation and angiogenesis in oral squamous cell carcinoma. Head Neck. 2013;35:250-256.

[126] Ruiz LM, Libedinsky A, Elorza AA. Role of copper on mitochondrial function and metabolism. Front Mol Biosci. 2021;8:711227.

[127] Shanbhag VC, Gudekar N, Jasmer K, Papageorgiou C, Singh K, Petris MJ. Copper metabolism as a unique vulnerability in cancer. Biochim Biophys Acta Mol Cell Res. 2021;1868:118893.

[128] Leary SC, Sasarman F, Nishimura T, Shoubridge EA. Human SCO2 is required for the synthesis of CO II and as a thiol-disulphide oxidoreductase for SCO1. Hum Mol Genet. 2009;18:2230-2240.

[129] Attardi G, Schatz G. Biogenesis of mitochondria. Annu Rev Cell Biol. 1988;4:289-333.

[130] Ussakli CH, Ebaee A, Binkley J, et al. Mitochondria and tumor progression in ulcerative colitis. J Natl Cancer Inst. 2013;105:1239-1248.

[131] Zhang K, Chen Y, Huang X, et al. Expression and clinical significance of cytochrome c oxidase subunit IV in colorectal cancer patients. Arch Med Sci. 2016;12:68-77.

[132] Hewedi IH, Farid RM, Sidhom KF, Salman MI, Mostafa RG. Differential expression of cytochrome C oxidase subunit I along the colorectal adenoma: carcinoma progression. Appl Immunohistochem Mol Morphol. 2018;26:689-696.

[133] Sacconi S, Trevisson E, Pistollato F, et al. hCOX18 and hCOX19: two human genes involved in cytochrome c oxidase assembly. Biochem Biophys Res Commun. 2005;337:832-839.

[134] Guo Q, Zhang H, Zhang L, et al. MicroRNA-21 regulates non-small cell lung cancer cell proliferation by affecting cell apoptosis via COX-19. Int J Clin Exp Med. 2015;8:8835-8841.

[135] Li J-P, Liu Y-J, Zeng S-H, Gao H-J, Chen Y-G, Zou X. Identification of COX4I2 as a hypoxia-associated gene acting through FGF1 to promote EMT and angiogenesis in CRC. Cell Mol Biol Lett. 2022;27:76.

[136] Gao S, Zhang H, Zhang X, Wang J, Bai W, Jiang B. COX19 is a new target of MACC1 and promotes colorectal cancer progression by regulating copper transport in mitochondria. J Nutr. 2024;154:381-394.

[137] Cordano A, Placko RP, Graham GG. Hypocupremia and neutropenia in copper deficiency. Blood. 1966;28:280-283.

[138] Dunlap WM, James GW, Hume DM. Anemia and neutropenia caused by copper deficiency. Ann Intern Med. 1974;80:470-476.

[139] Ashkenazi A, Levin S, Djaldetti M, Fishel E, Benvenisti D. The syndrome of neonatal copper deficiency. Pediatrics. 1973;52:525-533.

[140] White C, Lee J, Kambe T, Fritsche K, Petris MJ. A role for the ATP7A copper-transporting ATPase in macrophage bactericidal activity. J Biol Chem. 2009;284:33949-33956.

[141] Stafford SL, Bokil NJ, Achard MES, et al. Metal ions in macrophage antimicrobial pathways: emerging roles for zinc and copper. Biosci Rep. 2013;33:e00049.

[142] Flynn A, Yen BR. Mineral deficiency effects on the generation of cytotoxic T-cells and T-helper cell factors in vitro. J Nutr. 1981;111:907-913.

[143] Crowe A, Jackaman C, Beddoes KM, Ricciardo B, Nelson DJ. Rapid copper acquisition by developing murine mesothelioma: decreasing bioavailable copper slows tumor growth, normalizes vessels and promotes T cell infiltration. PLoS One. 2013;8:e73684.

[144] Gundelach JH, Madhavan AA, Wettstein PJ, Bram RJ. The anticancer drug Dp44mT inhibits T-cell activation and CD25 through a copper-dependent mechanism. FASEB J. 2013;27:782-792.

[145] He R, Zhang H, Zhao H, et al. Multiomics analysis reveals cuproptosis-related signature for evaluating prognosis and immunotherapy efficacy in colorectal cancer. Cancers (Basel). 2023;15:387.

[146] Zhang B, Li Y, Song L, et al. Cuproplasia characterization in colon cancer assists to predict prognosis and immunotherapeutic response. Front Oncol. 2023;13:1061084.

[147] Li S, Zhu Z, Lu J, et al. Prediction of prognosis, immune infiltration, and personalized treatment of hepatocellular carcinoma by analysis of cuproptosis-related long noncoding RNAs and verification in vitro. Front Oncol. 2023;13:1159126.

[148] Wang L, Cao Y, Guo W, Xu J. High expression of cuproptosis-related gene FDX1 in relation to good prognosis and immune cells infiltration in colon adenocarcinoma (COAD). J Cancer Res Clin Oncol. 2023;149:15-24.

[149] Xu L, Wu P, Rong A, et al. Systematic pan-cancer analysis identifies cuproptosis-related gene DLAT as an immunological and prognostic biomarker. Aging (Albany NY). 2023;15:4269-4287.

[150] Gao F, Yuan Y, Ding Y, Li P-Y, Chang Y, He X-X. DLAT as a cuproptosis promoter and a molecular target of elesclomol in hepatocellular carcinoma. Curr Med Sci. 2023;43:526-538.

[151] Chu B, Wang Y, Yang J, Dong B. Integrative analysis of single-cell and bulk RNA seq to reveal the prognostic model and tumor microenvironment remodeling mechanisms of cuproptosis-related genes in colorectal cancer. Aging (Albany NY). 2023;15:14422-14444.

[152] Sun L, Zhang Y, Yang B, et al. Lactylation of METTL16 promotes cuproptosis via m(6)A-modification on FDX1 mRNA in gastric cancer. Nat Commun. 2023;14:6523.

[153] Wang W, Lu K, Jiang X, et al. Ferroptosis inducers enhanced cuproptosis induced by copper ionophores in primary liver cancer. J Exp Clin Cancer Res. 2023;42:142.

[154] Huang Y, Yin D, Wu L. Identification of cuproptosis-related subtypes and development of a prognostic signature in colorectal cancer. Sci Rep. 2022;12:17348.

[155] Du Y, Lin Y, Wang B, et al. Cuproptosis patterns and tumor immune infiltration characterization in colorectal cancer. Front Genet. 2022;13:976007.

[156] Jiang P-C, Fan J, Zhang C-D, et al. Unraveling colorectal cancer and pan-cancer immune heterogeneity and synthetic therapy response using cuproptosis and hypoxia regulators by multi-omic analysis and experimental validation. Int J Biol Sci. 2023;19:3526-3543.

[157] Wu W, Dong J, Lv Y, Chang D. Cuproptosis-Related genes in the prognosis of colorectal cancer and their correlation with the tumor microenvironment. Front Genet. 2022;13:984158.

[158] Zhu Z, Zhao Q, Song W, et al. A novel cuproptosis-related molecular pattern and its tumor microenvironment characterization in colorectal cancer. Front Immunol. 2022;13:940774.

[159] Huang H, Long Z, Xie Y, et al. Molecular subtypes based on cuproptosis-related genes and tumor microenvironment infiltration characterization in colorectal cancer. J Oncol. 2022;2022:5034092.

[160] Zhu Z, Guo T, Weng J, et al. Cuproptosis-related miRNAs signature and immune infiltration characteristics in colorectal cancer. Cancer Med. 2023;12:16661-16678.

[161] Yang W, Wang Y, Huang Y, et al. 4-Octyl itaconate inhibits aerobic glycolysis by targeting GAPDH to promote cuproptosis in colorectal cancer. Biomed Pharmacother. 2023;159:114301.

[162] Zhou L, Zhang Y, Xu Y, Jiang T, Tang L. Identification of a novel prognostic signature composed of 3 cuproptosis-related transcription factors in colon adenocarcinoma. Genes Genomics. 2023;45:1047-1061.

[163] Wang C, Guo J, Zhang Y, Zhou S, Jiang B. Cuproptosis-related gene FDX1 suppresses the growth and progression of colorectal cancer by retarding EMT progress. Biochem Genet. 2024.

[164] Wu Z, Guo J, Zhang Y, et al. TIGD1 function as a potential cuproptosis regulator following a novel cuproptosis-related gene risk signature in colorectal cancer. Cancers (Basel). 2023;15:2286.

[165] Xue Q, Kang R, Klionsky DJ, Tang D, Liu J, Chen X. Copper metabolism in cell death and autophagy. Autophagy. 2023;19:2175-2195.

[166] Ding X, Xie H, Kang YJ. The significance of copper chelators in clinical and experimental application. J Nutr Biochem. 2011;22:301-310.

[167] Cui H, Zhang AJ, Mckeage MJ, et al. Copper transporter 1 in human colorectal cancer cell lines: effects of endogenous and modified expression on oxaliplatin cytotoxicity. J Inorg Biochem. 2017;177:249-258.

[168] Gartner EM, Griffith KA, Pan Q, et al. A pilot trial of the anti-angiogenic copper lowering agent tetrathiomolybdate in combination with irinotecan, 5-flurouracil, and leucovorin for metastatic colorectal cancer. Invest New Drugs. 2009;27:159-165.

[169] Baldari S, Di Rocco G, Heffern MC, Su TA, Chang CJ, Toietta G. Effects of copper chelation on BRAF(V600E) positive colon carcinoma cells. Cancers (Basel). 2019;11:659.

[170] Möschl P, Lubec G. [5-fluorouracil inhibits the collagenolytic activity of invasive colonic adenocarcinomas in vitro]. Onkologie. 1978;1:149-151.

[171] Fatfat M, Merhi RA, Rahal O, et al. Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species. BMC Cancer. 2014;14:527.

[172] Yu N, Zhu H, Yang Y, et al. Combination of Fe/Cu-chelators and docosahexaenoic acid: an exploration for the treatment of colorectal cancer. Oncotarget. 2017;8:51478-51491.

[173] Yoshiji H, Yoshii J, Kuriyama S, et al. Combination of copper-chelating agent, trientine, and methotrexate attenuates colorectal carcinoma development and angiogenesis in mice. Oncol Rep. 2005;14:213-218.

[174] Aggarwal A, Bhatt M. Advances in treatment of wilson disease. Tremor Other Hyperkinet Mov (N Y). 2018;8:525.

[175] Blanusa M, Varnai VM, Piasek M, Kostial K. Chelators as antidotes of metal toxicity: therapeutic and experimental aspects. Curr Med Chem. 2005;12:2771-2794.

[176] Shi X, Li Y, Jia M, et al. A novel copper chelator for the suppression of colorectal cancer. Drug Dev Res. 2023;84:312-325.

[177] O'brien H, Davoodian T, Johnson MDL. The promise of copper ionophores as antimicrobials. Curr Opin Microbiol. 2023;75:102355.

[178] Oliveri V. Selective targeting of cancer cells by copper ionophores: an overview. Front Mol Biosci. 2022;9:841814.

[179] Hasinoff BB, Yadav AA, Patel D, Wu X. The cytotoxicity of the anticancer drug elesclomol is due to oxidative stress indirectly mediated through its complex with Cu(II). J Inorg Biochem. 2014;137:22-30.

[180] Feng Yi, Wu J-J, Sun Z-L, et al. Targeted apoptosis of myofibroblasts by elesclomol inhibits hypertrophic scar formation. EBioMedicine. 2020;54:102715.

[181] Huang C, Wang M, Wang J, et al. Suppression MGP inhibits tumor proliferation and reverses oxaliplatin resistance in colorectal cancer. Biochem Pharmacol. 2021;189:114390.

[182] Martinez-Balibrea E, Martínez-Cardús A, Musulén E, et al. Increased levels of copper efflux transporter ATP7B are associated with poor outcome in colorectal cancer patients receiving oxaliplatin-based chemotherapy. Int J Cancer. 2009;124:2905-2910.

[183] Zhou Y, Zhang Q, Wang M, Huang C, Yao X. Effective delivery of siRNA-loaded nanoparticles for overcoming oxaliplatin resistance in colorectal cancer. Front Oncol. 2022;12:827891.

[184] Johansson B. A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites. Acta Psychiatr Scand Suppl. 1992;369:15-26.

[185] Wang Y, Li W, Patel SS, et al. Blocking the formation of radiation-induced breast cancer stem cells. Oncotarget. 2014;5:3743-3755.

[186] Morrison BW, Doudican NA, Patel KR, Orlow SJ. Disulfiram induces copper-dependent stimulation of reactive oxygen species and activation of the extrinsic apoptotic pathway in melanoma. Melanoma Res. 2010;20:11-20.

[187] Li Y, Chen F, Chen J, et al. Disulfiram/copper induces antitumor activity against both nasopharyngeal cancer cells and cancer-associated fibroblasts through ROS/MAPK and ferroptosis pathways. Cancers (Basel). 2020;12:138.

[188] Cen D, Gonzalez RI, Buckmeier JA, Kahlon RS, Tohidian NB. Disulfiram induces apoptosis in human melanoma cells: a redox-related process. Mol Cancer Ther. 2002;1:197-204.

[189] Wang N-N, Wang L-H, Li Y, et al. Targeting ALDH2 with disulfiram/copper reverses the resistance of cancer cells to microtubule inhibitors. Exp Cell Res. 2018;362:72-82.

[190] Yang Z, Guo F, Albers AE, Sehouli J, Kaufmann AM. Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines. Biomed Pharmacother. 2019;113:108727.

[191] Ying H, Qin A, Cheng TS, et al. Disulfiram attenuates osteoclast differentiation in vitro: a potential antiresorptive agent. PLoS One. 2015;10:e0125696.

[192] Chiba T, Suzuki E, Yuki K, et al. Disulfiram eradicates tumor-initiating hepatocellular carcinoma cells in ROS-p38 MAPK pathway-dependent and -independent manners. PLoS One. 2014;9:e84807.

[193] Chen Di, Cui QC, Yang H, Dou QP. Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. Cancer Res. 2006;66:10425-10433.

[194] Skrott Z, Mistrik M, Andersen KK, et al. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature. 2017;552:194-199.

[195] Huang X, Hou Y, Weng X, et al. Diethyldithiocarbamate-copper complex (CuET) inhibits colorectal cancer progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis-mediated aerobic glycolysis pathway. Oncogenesis. 2021;10:4.

[196] Hu Y, Qian Y, Wei J, et al. The disulfiram/copper complex induces autophagic cell death in colorectal cancer by targeting ULK1. Front Pharmacol. 2021;12:752825.

[197] You S-Y, Rui W, Chen S-T, et al. Process of immunogenic cell death caused by disulfiram as the anti-colorectal cancer candidate. Biochem Biophys Res Commun. 2019;513:891-897.

[198] Navrátilová J, Hankeová T, Beneš P, Šmarda J. Acidic pH of tumor microenvironment enhances cytotoxicity of the disulfiram/Cu2+ complex to breast and colon cancer cells. Chemotherapy. 2013;59:112-120.

[199] Guo X, Xu B, Pandey S, et al. Disulfiram/copper complex inhibiting NFkappaB activity and potentiating cytotoxic effect of gemcitabine on colon and breast cancer cell lines. Cancer Lett. 2010;290:104-113.

[200] Hendrych M, Říhová K, Adamová B, et al. Disulfiram increases the efficacy of 5-fluorouracil in organotypic cultures of colorectal carcinoma. Biomed Pharmacother. 2022;153:113465.

[201] Zhang P, Zhou C, Ren X, et al. Inhibiting the compensatory elevation of xCT collaborates with disulfiram/copper-induced GSH consumption for cascade ferroptosis and cuproptosis. Redox Biol. 2024;69:103007.

[202] Jiapaer Z, Zhang L, Ma W, et al. Disulfiram-loaded hollow copper sulfide nanoparticles show anti-tumor effects in preclinical models of colorectal cancer. Biochem Biophys Res Commun. 2022;635:291-298.

[203] Najlah M, Said Suliman A, Tolaymat I, et al. Development of injectable PEGylated liposome encapsulating disulfiram for colorectal cancer treatment. Pharmaceutics. 2019;11:610.

[204] Jiang Y, Huo Z, Qi X, Zuo T, Wu Z. Copper-induced tumor cell death mechanisms and antitumor theragnostic applications of copper complexes. Nanomedicine (Lond). 2022;17:303-324.

[205] Tsymbal S, Li Ge, Agadzhanian N, et al. Recent advances in copper-based organic complexes and nanoparticles for tumor theranostics. Molecules. 2022;27:7066.

[206] Dam J, Ismail Z, Kurebwa T, et al. Synthesis of copper and zinc 2-(pyridin-2-yl)imidazo[1,2-a]pyridine complexes and their potential anticancer activity. Eur J Med Chem. 2017;126:353-368.

[207] Kubiak K, Malinowska K, Langer E, Dziki Ł, Dziki A, Majsterek I. Effect of Cu(II) coordination compounds on the activity of antioxidant enzymes catalase and superoxide dismutase in patients with colorectal cancer. Pol Przegl Chir. 2011;83:155-160.

[208] Sandhaus S, Taylor R, Edwards T, et al. A novel copper(II) complex identified as a potent drug against colorectal and breast cancer cells and as a poison inhibitor for human topoisomerase IIalpha. Inorg Chem Commun. 2016;64:45-49.

[209] Mendo AS, Figueiredo S, Roma-Rodrigues C, et al. Characterization of antiproliferative potential and biological targets of a copper compound containing 4'-phenyl terpyridine. J Biol Inorg Chem. 2015;20:935-948.

[210] Hajrezaie M, Paydar M, Zorofchian Moghadamtousi S, et al. A Schiff base-derived copper (II) complex is a potent inducer of apoptosis in colon cancer cells by activating the intrinsic pathway. ScientificWorldJournal. 2014;2014:540463.

[211] Pellei M, Gandin V, Cimarelli C, et al. Syntheses and biological studies of nitroimidazole conjugated heteroscorpionate ligands and related Cu(I) and Cu(II) complexes. J Inorg Biochem. 2018;187:33-40.

[212] Lesiów MK, Komarnicka UK, Stokowa-Sołtys K, et al. Relationship between copper(II) complexes with FomA adhesin fragments of F. nucleatum and colorectal cancer. Coordination pattern and ability to promote ROS production. Dalton Trans. 2018;47:5445-5458.

[213] Lim H, Oh C, Park M-S, et al. Hint from an enzymatic reaction: superoxide dismutase models efficiently suppress colorectal cancer cell proliferation. J Am Chem Soc. 2023;145:16058-16068.

[214] Ng CH, Kong SM, Tiong YL, et al. Selective anticancer copper(II)-mixed ligand complexes: targeting of ROS and proteasomes. Metallomics. 2014;6:892-906.

[215] Ruiz MC, Perelmulter K, Levín P, et al. Antiproliferative activity of two copper (II) complexes on colorectal cancer cell models: impact on ROS production, apoptosis induction and NF-kappaB inhibition. Eur J Pharm Sci. 2022;169:106092.

[216] Liu Z, Fan L, Niu D, et al. Copper (II) complex of salicylate phenanthroline induces the apoptosis of colorectal cancer cells, including oxaliplatin‑resistant cells. Oncol Rep. 2023;50:170.

[217] Arikrishnan S, Loh JS, Teo XW, et al. Ternary copper (II) complex induced apoptosis and cell cycle arrest in colorectal cancer cells. Anticancer Agents Med Chem. 2022;22:999-1011.

[218] Harmse L, Gangat N, Martins-Furness C, Dam J, De Koning CB. Copper-imidazo[1,2-a]pyridines induce intrinsic apoptosis and modulate the expression of mutated p53, haem-oxygenase-1 and apoptotic inhibitory proteins in HT-29 colorectal cancer cells. Apoptosis. 2019;24:623-643.

[219] Rashid A, Ananthnag GS, Naik S, Mague JT, Panda D, Balakrishna MS. Dinuclear Cu(I) complexes of pyridyl-diazadiphosphetidines and aminobis(phosphonite) ligands: synthesis, structural studies and antiproliferative activity towards human cervical, colon carcinoma and breast cancer cells. Dalton Trans. 2014;43:11339-11351.

[220] Ali A, Mishra S, Kamaal S, et al. Evaluation of catacholase mimicking activity and apoptosis in human colorectal carcinoma cell line by activating mitochondrial pathway of copper(II) complex coupled with 2-(quinolin-8-yloxy)(methyl)benzonitrile and 8-hydroxyquinoline. Bioorg Chem. 2021;106:104479.

[221] Gandin V, Pellei M, Tisato F, Porchia M, Santini C, Marzano C. A novel copper complex induces paraptosis in colon cancer cells via the activation of ER stress signalling. J Cell Mol Med. 2012;16:142-151.

[222] Sequeira D, Baptista PV, Valente R, et al. Cu(I) complexes as new antiproliferative agents against sensitive and doxorubicin resistant colorectal cancer cells: synthesis, characterization, and mechanisms of action. Dalton Trans. 2021;50:1845-1865.

[223] Shen W, Pei P, Zhang C, et al. A polymeric hydrogel to eliminate programmed death-ligand 1 for enhanced tumor radio-immunotherapy. ACS Nano. 2023;17:23998-24011.

[224] Pei P, Wang Y, Shen W, et al. Oxygen-driven cuproptosis synergizes with radiotherapy to potentiate tumor immunotherapy. Aggregate. 2024:e484.

[225] Chang M, Hou Z, Jin D, et al. Colorectal tumor microenvironment-activated bio-decomposable and metabolizable Cu(2) O@CaCO(3) nanocomposites for synergistic oncotherapy. Adv Mater. 2020;32:e2004647.

[226] Al-Zharani M, Qurtam AA, Daoush WM, et al. Antitumor effect of copper nanoparticles on human breast and colon malignancies. Environ Sci Pollut Res Int. 2021;28:1587-1595.

[227] Ghasemi P, Shafiee G, Ziamajidi N, Abbasalipourkabir R. Copper Nanoparticles induce apoptosis and oxidative stress in SW480 human colon cancer cell line. Biol Trace Elem Res. 2023;201:3746-3754.

[228] Gnanavel V, Palanichamy V, Roopan SM. Biosynthesis and characterization of copper oxide nanoparticles and its anticancer activity on human colon cancer cell lines (HCT-116). J Photochem Photobiol B. 2017;171:133-138.

[229] Khan S, Ansari AA, Khan AA, Abdulla M, Al-Obaid O, Ahmad R. In vitro evaluation of cytotoxicity, possible alteration of apoptotic regulatory proteins, and antibacterial activity of synthesized copper oxide nanoparticles. Colloids Surf B Biointerfaces. 2017;153:320-326.

[230] Liu Z, Xiong L, Ouyang G, et al. Investigation of copper cysteamine nanoparticles as a new type of radiosensitiers for colorectal carcinoma treatment. Sci Rep. 2017;7:9290.

[231] Li J, Zhang Z, Li J, et al. Copper-olsalazine metal-organic frameworks as a nanocatalyst and epigenetic modulator for efficient inhibition of colorectal cancer growth and metastasis. Acta Biomater. 2022;152:495-506.

[232] Gholami M, Darroudi M, Hekmat A, Khazaei M. Five-FU@CuS/NH(2) -UiO-66 as a drug delivery system for 5-fluorouracil to colorectal cancer cells. J Biochem Mol Toxicol. 2022;36:e23145.

[233] Gholami M, Hekmat A, Khazaei M, Darroudi M. OXA-CuS@UiO-66-NH(2) as a drug delivery system for Oxaliplatin to colorectal cancer cells. J Mater Sci Mater Med. 2022;33:26.

[234] Xiong K, Zhou Y, Karges J, et al. Autophagy-dependent apoptosis induced by apoferritin-Cu(II) nanoparticles in multidrug-resistant colon cancer cells. ACS Appl Mater Interfaces. 2021;13:38959-38968.

[235] Anderson CJ, Schwarz SW, Connett JM, et al. Preparation, biodistribution and dosimetry of copper-64-labeled anti-colorectal carcinoma monoclonal antibody fragments 1A3-F(ab')2. J Nucl Med. 1995;36:850-858.

[236] Liu D, Overbey D, Watkinson LD, et al. Comparative evaluation of three 64Cu-labeled E. coli heat-stable enterotoxin analogues for PET imaging of colorectal cancer. Bioconjug Chem. 2010;21:1171-1176.

[237] Zhou B, Wang H, Liu R, et al. PET imaging of Dll4 expression in glioblastoma and colorectal cancer xenografts using (64)Cu-labeled monoclonal antibody 61B. Mol Pharm. 2015;12:3527-3534.

[238] Paudyal B, Paudyal P, Oriuchi N, Hanaoka H, Tominaga H, Endo K. Positron emission tomography imaging and biodistribution of vascular endothelial growth factor with 64Cu-labeled bevacizumab in colorectal cancer xenografts. Cancer Sci. 2011;102:117-121.

[239] Philpott GW, Schwarz SW, Anderson CJ, et al. RadioimmunoPET: detection of colorectal carcinoma with positron-emitting copper-64-labeled monoclonal antibody. J Nucl Med. 1995;36:1818-1824.

[240] Beaino W, Guo Y, Chang AJ, Anderson CJ. Roles of Atox1 and p53 in the trafficking of copper-64 to tumor cell nuclei: implications for cancer therapy. J Biol Inorg Chem. 2014;19:427-438.

[241] Delaloye AB, Delaloye B, Buchegger F, et al. Comparison of copper-67- and iodine-125-labeled anti-CEA monoclonal antibody biodistribution in patients with colorectal tumors. J Nucl Med. 1997;38:847-853.

[242] Nittka S, Krueger MA, Shively JE, et al. Radioimmunoimaging of liver metastases with PET using a 64Cu-labeled CEA antibody in transgenic mice. PLoS One. 2014;9:e106921.

[243] Khosravifarsani M, Ait-Mohand S, Paquette B, Sanche L, Guérin B. Design, synthesis, and cytotoxicity assessment of [(64)Cu]Cu-NOTA-terpyridine platinum conjugate: a novel chemoradiotherapeutic agent with flexible linker. Nanomaterials (Basel). 2021;11:2154.

[244] Khosravifarsani M, Ait-Mohand S, Paquette B, Sanche L, Guérin B. In vivo behavior of [(64)Cu]NOTA-terpyridine platinum, a novel chemo-radio-theranostic agent for imaging, and therapy of colorectal cancer. Front Med (Lausanne). 2022;9:975213.

[245] Achmad A, Hanaoka H, Yoshioka H, et al. Predicting cetuximab accumulation in KRAS wild-type and KRAS mutant colorectal cancer using 64Cu-labeled cetuximab positron emission tomography. Cancer Sci. 2012;103:600-605.

[246] Zeng D, Guo Y, White AG, et al. Comparison of conjugation strategies of cross-bridged macrocyclic chelators with cetuximab for copper-64 radiolabeling and PET imaging of EGFR in colorectal tumor-bearing mice. Mol Pharm. 2014;11:3980-3987.

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