Copper promotes the formation of blood vessels, including those that supply tumors. Depleting copper can deprive the tumor of a blood supply of oxygen and nutrients.
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Modes of action
Copper levels in blood plasma are significantly increased in neoplasias in the stomach, large intestine and lungs.1Scanni A, Licciardello L, Trovato M, Tomirotti M, Biraghi M. Serum copper and ceruloplasmin levels in patients with neoplasias localized in the stomach, large intestine or lung. Tumori. 1977;63(2):175–180. As disease progresses, copper levels further increase, and they decline with remission.2Scanni A, Tomirotti M et al. Variations in serum copper and ceruloplasmin levels in advanced gastrointestinal cancer treated with polychemotherapy. Tumori. 1979;65(3):331–338.
Intratumoral copper levels influence PD-L1 expression in cancer cells, and copper regulates key signaling pathways mediating PD-L1-driven cancer immune evasion. Copper chelators inhibited phosphorylation of STAT3 and EGFR and promoted ubiquitin-mediated degradation of PD-L1.3Voli F, Valli E et al. Intratumoral copper modulates pd-l1 expression and influences tumor immune evasion. Cancer Research. 2020 Oct 1;80(19):4129-4144.
The inflammatory response induces copper uptake through an IL-17-STEAP4-XIAP axis, promoting colon tumorigenesis.4Liao Y, Zhao J et al. Inflammation mobilizes copper metabolism to promote colon tumorigenesis via an IL-17-STEAP4-XIAP axis. Nature Communications. 2020 Feb 14;11(1):900.
Preclinical evidence
The strongest preclinical evidence for each cancer type is presented here; clinical evidence is in How can copper chelation help you? What the research says ›
Improving treatment outcomes
Zinc-carnosine metallodrug network nanoparticles, a dual metabolism inhibitor, exerted more efficient metabolism-targeted therapy than the classic copper chelator, tetrathiomolybdate (TM), in both breast cancer (sensitive to copper depletion) and colon cancer (less sensitive to copper depletion) models.5Lei L, Nan B et al. Zinc-carnosine metallodrug network as dual metabolism inhibitor overcoming metabolic reprogramming for efficient cancer therapy. Nano Letters. 2023 Apr 12;23(7):2659-2668.
Cancer as a whole
- A nanohybrid comprising 3-azidopropylamine, 4-ethynylaniline, and N-aminoethyl-N’-benzoylthiourea (BTU) co-modified gold nanoparticles (AuNPs) caused copper deficiency, inhibiting vascularization and tumor migration and leading to a high survival rate of tumor-bearing mice after application.6Yin T, Yang T et al. Intelligent gold nanoparticles for malignant tumor treatment via spontaneous copper manipulation and on-demand photothermal therapy based on copper induced click chemistry. Acta Biomaterialia. 2023 Aug;166:485-495.
- A copper chelate of Schiff base, copper (II)-N-(2-hydroxy-3-methoxy-benzaldehyde)-alaninate (CuPHMBA), kills both the drug-resistant and sensitive cancer cell types irrespective of their drug resistance phenotype.7Banerjee K, Basu S et al. Induction of intrinsic and extrinsic apoptosis through oxidative stress in drug-resistant cancer by a newly synthesized Schiff base copper chelate. Free Radical Research. 2016;50(4):426-46.
- Copper chelators decreased tumor growth of human or murine cells transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition.8Brady DC, Crowe MS et al. Copper is required for oncogenic BRAF signalling and tumorigenesis. Nature. 2014 May 22;509(7501):492-6.
- The antiproliferative effect of copper chelation was enhanced when combined with inhibitors of glycolysis.9Ishida S, Andreux P, Poitry-Yamate C, Auwerx J, Hanahan D. Bioavailable copper modulates oxidative phosphorylation and growth of tumors. Proceedings of the National Academy of Sciences of the USA. 2013 Nov 26;110(48):19507-12.
- Copper-lowering agents reduced hCtr1-associated resistance to cisplatin in a variety of cancer cells.10Liang ZD, Long Y et al. Mechanistic basis for overcoming platinum resistance using copper chelating agents. Molecular Cancer Therapies. 2012 Nov;11(11):2483-94.
- Adding the copper chelator ATN-224 to herpes simplex virus-derived oncolytic viruses (oHSV) to treat tumor growth increased serum stability of oHSV and greatly enhanced its replication and antitumor efficacy.11Yoo JY, Pradarelli J et al. Copper chelation enhances antitumor efficacy and systemic delivery of oncolytic HSV. Clinical Cancer Research. 2012 Sep 15;18(18):4931-41.
Brain cancer
- Tetrathiomolybdate (TM) decreased metastases to lungs, LOX activity, and collagen crosslinking in MDA-LM2-luciferase cells in mice.12Chan N, Willis A et al. Influencing the tumor microenvironment: a phase II study of copper depletion using tetrathiomolybdate in patients with breast cancer at high risk for recurrence and in preclinical models of lung metastases. Clinical Cancer Research. 2017 Feb 1;23(3):666-676.
- D-Pen inhibits gliosarcoma tumor growth in animals and is an effective antiangiogenic agent in gliomas in rats.13Gupte A, Mumper RJ. Elevated copper and oxidative stress in cancer cells as a target for cancer treatment. Cancer Treatment Reviews. 2009;35(1):32–46.
Breast cancer
- Copper deficiency impaired tumor growth and angiogenesis in an inflammatory breast cancer xenograft and in Her2/neu cancer-prone transgenic mice.14Pan Q, Kleer CG et al. Copper deficiency induced by tetrathiomolybdate suppresses tumor growth and angiogenesis. Cancer Research. 2002 Sep 1;62(17):4854-9.
- Copper depletion inhibited tumor growth and substantially improved survival of triple-negative breast cancer in mice.15Cui L, Gouw AM et al. Mitochondrial copper depletion suppresses triple-negative bre ast cancer in mice. Nature Biotechnology. 2021 Mar;39(3):357-367.
- A redox-responsive paclitaxel (PTX) prodrug conjugating PTX with a copper chelator through a disulfide bond generated an enhanced therapeutic outcome toward triple-negative breast cancer.16Hao D, Meng Q et al. A paclitaxel prodrug with copper depletion for combined therapy toward triple-negative breast cancer. ACS Nano. 2023 Jul 11;17(13):12383-12393.
- Copper chelation restored cytotoxic activity of anthracyclines.17Wiegmans AP, Saunus JM et al. Secreted cellular prion protein binds doxorubicin and correlates with anthracycline resistance in breast cancer. JCI Insight. 2019 Feb 26;5(6):e124092.
Cervical cancer
- Ligand-L, a pregnenolone acetate nucleus-based tetrazole derivative that chelates copper, exhibits significant cytotoxic activity against cervical cancer cells, inducing pro-oxidant death.18Zafar A, Singh S et al. Interaction of C20-substituted derivative of pregnenolone acetate with copper (II) leads to ROS generation, DNA cleavage and apoptosis in cervical cancer cells: Therapeutic potential of copper chelation for cancer treatment. Bioorganic Chemistry. 2019 Jun;87:276-290.
Colon cancer
- Copper chelation showed antitumor activity in human colon cancer cells grafted onto mice.19Fatfat M, Merhi RA et al. Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species. BMC Cancer. 2014;14:527.
- Copper chelation affected proliferation, survival, and migration in colorectal cancer cells with BRAF mutation, a gene mutation which may increase the growth and spread of cancer cells. Copper chelation also decreased the cloning potential of BRAF cells otherwise resistant to drugs targeting the BRAF mutation.20Baldari S, Di Rocco G et al. Effects of copper chelation on BRAFV600E positive colon carcinoma cells. Cancers (Basel). 2019;11(5):659.
- The copper chelator elesclomol promotes the degradation of the copper transporter copper-transporting ATPase 1 (ATP7A), which retards the proliferation of colorectal cancer cells.21Gao W, Huang Z et al. Elesclomol induces copper-dependent ferroptosis in colorectal cancer cells via degradation of ATP7A. Molecular Oncology. 2021 Dec;15(12):3527-3544.
- Melon extracts, especially melon peel aqueous extract, showed copper-chelating properties in lab studies.22Rolim PM, Fidelis GP et al. Phenolic profile and antioxidant activity from peels and seeds of melon (Cucumis melo L. var. reticulatus) and their antiproliferative effect in cancer cells. Brazilian Journal of Medical and Biological Research. 2018;51(4):e6069.
- Copper chelators plus iron chelators combined with DHA and 5-FU in colorectal cancer cells overcame drug resistance through apoptosis.23Yu N, Zhu H et al. Combination of Fe/Cu -chelators and docosahexaenoic acid: an exploration for the treatment of colorectal cancer. Oncotarget. 2017;8(31):51478–51491.
Head and neck cancer
- Pretreatment with either of 2 copper chelators, cuprizone or bathocuproine sulphonate, significantly increased cisplatin’s sensitivity in squamous cell carcinoma of the head and neck SCCHN), particularly in the context of TMEM16A overexpression.24Vyas A, Duvvuri U, Kiselyov K. Copper-dependent ATP7B up-regulation drives the resistance of TMEM16A-overexpressing head-and-neck cancer models to platinum toxicity. Biochemical Journal. 2019 Dec 19;476(24):3705-3719.
Leukemia
- D-Penicillamine (D-pen), a copper-chelating agent, in the presence of cupric sulfate resulted in concentration-dependent cytotoxicity.25Gupte A, Mumper RJ. Copper chelation by D-penicillamine generates reactive oxygen species that are cytotoxic to human leukemia and breast cancer cells. Free Radical Biology & Medicine. 2007 Nov 1;43(9):1271-8.
Liver cancer
- Copper chelation forestalled hepatocellular tumor cell survival after exposure to hypoxia.26Davis CI, Gu X et al. Altered copper homeostasis underlies sensitivity of hepatocellular carcinoma to copper chelation. Metallomics. 2020 Dec 23;12(12):1995-2008.
Lung cancer
- Copper chelation therapy inhibited both autophagy and MAPK signaling in BRAFV600E-driven lung adenocarcinoma cells.27Tsang T, Gu X et al. BRAFV600E-driven lung adenocarcinoma requires copper to sustain autophagic signaling and processing. Molecular Cancer Research. 2022 Jul 6;20(7):1096-1107.
- Curcumin inhibits copper influx and increases uptake of platinum ions in non-small cell lung cancer tumors.28Zhang W, Shi H et al. Curcumin enhances cisplatin sensitivity of human NSCLC cell lines through influencing Cu-Sp1-CTR1 regulatory loop. Phytomedicine. 2018 Sep 15;48:51-61.
Melanoma
- Casuarictin (CAS), isolated from clove extracts, possessed robust copper chelating ability and inhibited intracellular melanogenesis in mouse melanoma cells.29Goenka S, Ceccoli J, Simon SR. Anti-melanogenic activity of ellagitannin casuarictin in B16F10 mouse melanoma cells. Natural Product Research. 2021 Jun;35(11):1830-1835.
- The copper chelator 5,6,7,8-tetrahydro-4H-furo[3,2-c]azepine-4-thione (T4FAT), a thioamide derivative, inhibited melanogenesis in mouse melanoma cells.30Okajima S, Hamamoto A et al. Azepine derivative T4FAT, a new copper chelator, inhibits tyrosinase. Biochemical and Biophysical Research Communications. 2019 Jan 29;509(1):209-215.
- Tetrathiomolybdate (TM) inhibited transformed growth of melanoma cell lines resistant to BRAF or MEK1/2 inhibitors and enhanced the antineoplastic activity of these inhibitors.31Brady DC, Crowe MS, Greenberg DN, Counter CM. Copper chelation inhibits BRAFV600E-driven melanomagenesis and counters resistance to BRAFV600E and MEK1/2 inhibitors. Cancer Research. 2017 Nov 15;77(22):6240-6252.
- D-Pen inhibits melanoma tumor growth in animals.32Gupte A, Mumper RJ. Elevated copper and oxidative stress in cancer cells as a target for cancer treatment. Cancer Treatment Reviews. 2009;35(1):32–46.
Pancreatic cancer
- Intracellular copper deprivation induced by CTR1 gene knock-down or systematic copper chelation by tetrathiomolybdate suppressed proliferation and angiogenesis of pancreatic cancer cells.33Geng R, Ke N et al. Copper deprivation enhances the chemosensitivity of pancreatic cancer to rapamycin by mTORC1/2 inhibition. Chemico-Biological Interactions. 2023 Sep 1;382:110546.
Prostate cancer
- Anticancer effects in prostate cancer cells from pyrrolidine dithiocarbamate (PDTC) but not TM34Chen D, Peng F et al. Inhibition of prostate cancer cellular proteasome activity by a pyrrolidine dithiocarbamate-copper complex is associated with suppression of proliferation and induction of apoptosis. Frontiers in Bioscience. 2005 Sep 1;10:2932-9.
Thyroid cancer
- Tetrathiomolybdate (TM) was as or more potent than lenvatinib and sorafenib and enhanced the antineoplastic activity of sorafenib and vemurafenib on papillary thyroid cancer cells, and TM as a maintenance therapy after cessation of vemurafenib reduced tumor volume.35Xu M, Casio M, Range DE, Sosa JA, Counter CM. Copper chelation as targeted therapy in a mouse model of oncogenic BRAF-driven papillary thyroid cancer. Clinical Cancer Research. 2018 Sep 1;24(17):4271-4281.
Optimizing your body terrain
Copper chelation shows these body terrain impacts in preclinical studies:
- Antioxidant: Excess copper is a potent oxidant, causing the generation of harmful reactive oxygen species (ROS) in cells. These ROSs are known to drive cancer development and growth.36Gupte A, Mumper RJ. Elevated copper and oxidative stress in cancer cells as a target for cancer treatment. Cancer Treatment Reviews. 2009;35(1):32–46.
- Immune function: Improved immune pathway response in animals37Khan G, Merajver S. Copper chelation in cancer therapy using tetrathiomolybdate: an evolving paradigm. Expert Opinion on Investigational Drugs. 2009;18(4):541–548.
- Anti-inflammatory effects in animal studies38Brewer GJ. Anticopper therapy against cancer and diseases of inflammation and fibrosis. Drug Discovery Today. 2005;10(16):1103–1109.
Professional commentary
Helpful links for professionals
Shanbhag VC, Gudekar N et al. Copper metabolism as a unique vulnerability in cancer. Biochimica et Biophysica Acta. Molecular Cell Research. 2021 Feb;1868(2):118893.
Tsang T, Posimo JM et al. Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma. Nature Cell Biology. 2020 Apr;22(4):412-424.
Rieber M. Cancer pro-oxidant therapy through copper redox cycling: repurposing disulfiram and tetrathiomolybdate. Current Pharmaceutical Design. 2020;26(35):4461-4466.
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