# Iron and Copper Intracellular Chelation as an Anticancer Drug Strategy **Authors:** Kavita Gaur, Alexandra M. Vázquez-Salgado, Geraldo Duran-Camacho, Irivette Dominguez-Martinez, Josué A. Benjamín-Rivera, Lauren Fernández-Vega, Lesly Carmona Sarabia, Angelys Cruz García, Felipe Pérez-Deliz, José A. Méndez Román, Melissa Vega-Cartagena, Sergio A. Loza-Rosas, Xaymara Rodriguez Acevedo, Arthur D. Tinoco PMC · DOI: 10.3390/inorganics6040126 · Inorganics · 2021-04-27 ## TL;DR This paper reviews how chelating iron and copper inside cancer cells can be a promising strategy for developing new anticancer drugs. ## Contribution The paper introduces a transmetallation strategy for dual targeting of copper and iron in cancer cells. ## Key findings - Copper and iron are essential for cancer cell proliferation and metastasis. - Certain chelators show promise in reducing the bioavailability of copper and iron in cancer cells. - Analytical tools are available to measure and track metal levels in cells and tissues. ## Abstract A very promising direction in the development of anticancer drugs is inhibiting the molecular pathways that keep cancer cells alive and able to metastasize. Copper and iron are two essential metals that play significant roles in the rapid proliferation of cancer cells and several chelators have been studied to suppress the bioavailability of these metals in the cells. This review discusses the major contributions that Cu and Fe play in the progression and spreading of cancer and evaluates select Cu and Fe chelators that demonstrate great promise as anticancer drugs. Efforts to improve the cellular delivery, efficacy, and tumor responsiveness of these chelators are also presented including a transmetallation strategy for dual targeting of Cu and Fe. To elucidate the effectiveness and specificity of Cu and Fe chelators for treating cancer, analytical tools are described for measuring Cu and Fe levels and for tracking the metals in cells, tissue, and the body. ## Linked entities - **Diseases:** cancer (MONDO:0004992) ## Full-text entities - **Genes:** AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, MAP2K1 (mitogen-activated protein kinase kinase 1) [NCBI Gene 5604] {aka CFC3, MAPKK1, MEK1, MEL, MKK1, PRKMK1}, SOD1 (superoxide dismutase 1) [NCBI Gene 6647] {aka ALS, ALS1, HEL-S-44, IPOA, SOD, STAHP}, MMP2 (matrix metallopeptidase 2) [NCBI Gene 4313] {aka CLG4, CLG4A, MMP-2, MMP-II, MONA, TBE-1}, CTR1 (high-affinity Cu transporter CTR1) [NCBI Gene 856241], RPTOR (regulatory associated protein of MTOR complex 1) [NCBI Gene 57521] {aka KOG1, Mip1}, COX1 (cytochrome c oxidase subunit I) [NCBI Gene 4512] {aka COI, MTCO1}, BRAF (B-Raf proto-oncogene, serine/threonine kinase) [NCBI Gene 673] {aka B-RAF1, B-raf, BRAF-1, BRAF1, NS7, RAFB1}, Mapk1 (mitogen-activated protein kinase 1) [NCBI Gene 26413] {aka 9030612K14Rik, ERK, Erk2, MAPK2, PRKM2, Prkm1}, MAP2K7 (mitogen-activated protein kinase kinase 7) [NCBI Gene 5609] {aka JNKK2, MAPKK7, MEK, MEK 7, MKK7, PRKMK7}, TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, Lrrc8d (leucine rich repeat containing 8D) [NCBI Gene 231549] {aka 2810473G09Rik, 4930525N13Rik, A930019F03, Lrrc5}, SP1 (Sp1 transcription factor) [NCBI Gene 6667], Lrrc8a (leucine rich repeat containing 8A VRAC subunit A) [NCBI Gene 241296] {aka Lrrc8, SWELL1, ebo, mKIAA1437}, SLC11A2 (solute carrier family 11 member 2) [NCBI Gene 4891] {aka AHMIO1, DCT1, DMT1, NRAMP2}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, HEPH (hephaestin) [NCBI Gene 9843] {aka CPL}, SLC31A1 (solute carrier family 31 member 1) [NCBI Gene 1317] {aka COPT1, CTR1, NSCT}, MMP14 (matrix metallopeptidase 14) [NCBI Gene 4323] {aka MMP-14, MMP-X1, MT-MMP, MT-MMP 1, MT1-MMP, MT1MMP}, NDRG1 (N-myc downstream regulated 1) [NCBI Gene 10397] {aka CAP43, CMT4D, DRG-1, DRG1, GC4, HMSNL}, TYR (tyrosinase) [NCBI Gene 7299] {aka ATN, CMM8, OCA1, OCA1A, OCAIA, SHEP3}, CCND1 (cyclin D1) [NCBI Gene 595] {aka BCL1, D11S287E, PRAD1, U21B31}, Atp7b (ATPase, copper transporting, beta polypeptide) [NCBI Gene 11979] {aka Atp7a, WND, tx}, CCS (copper chaperone for superoxide dismutase) [NCBI Gene 9973], ALB (albumin) [NCBI Gene 213] {aka FDAHT, HSA, PRO0883, PRO0903, PRO1341}, Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, SCO1 (synthesis of cytochrome C oxidase 1) [NCBI Gene 6341] {aka MC4DN4, SCOD1}, SLC40A1 (solute carrier family 40 member 1) [NCBI Gene 30061] {aka FPN, FPN1, HFE4, IREG1, MST079, MSTP079}, CTR2 (low-affinity Cu transporter) [NCBI Gene 856580], Trf (transferrin) [NCBI Gene 22041] {aka Cd176, HP, Tf, Tfn, hpx}, COMMD1 (copper metabolism domain containing 1) [NCBI Gene 150684] {aka C2orf5, MURR1}, OCT1 (metalloendopeptidase) [NCBI Gene 853724], ATP7A (ATPase copper transporting alpha) [NCBI Gene 538] {aka DSMAX, HMNX, MK, MNK, SMAX3}, MTF1 (metal regulatory transcription factor 1) [NCBI Gene 4520] {aka MTF-1, ZRF}, BSG (basigin (Ok blood group)) [NCBI Gene 682] {aka 5F7, CD147, EMMPRIN, EMPRIN, HAb18G, OK}, Vegfa (vascular endothelial growth factor A) [NCBI Gene 22339] {aka L-VEGF, Vegf, Vpf}, Map2k1 (mitogen-activated protein kinase kinase 1) [NCBI Gene 26395] {aka MAPKK1, MEKK1, Mek1, Prkmk1}, Slc31a1 (solute carrier family 31, member 1) [NCBI Gene 20529] {aka 4930445G01Rik, Ctr1}, ERBB2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 2064] {aka CD340, HER-2, HER-2/neu, HER2, MLN 19, MLN-19}, MAPK1 (mitogen-activated protein kinase 1) [NCBI Gene 5594] {aka ERK, ERK-2, ERK2, ERT1, MAPK2, NS13}, MTF2 (metal response element binding transcription factor 2) [NCBI Gene 22823] {aka M96, PCL2, TDRD19A, dJ976O13.2}, F3 (coagulation factor III, tissue factor) [NCBI Gene 2152] {aka CD142, TF, TFA}, Cxcl15 (C-X-C motif chemokine ligand 15) [NCBI Gene 20309] {aka Il8, Scyb15, lungkine, weche}, CDKN1A (cyclin dependent kinase inhibitor 1A) [NCBI Gene 1026] {aka CAP20, CDKN1, CIP1, MDA-6, P21, SDI1}, TF (transferrin) [NCBI Gene 7018] {aka HEL-S-71p, PRO1557, PRO2086, TFQTL1}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, TFRC (transferrin receptor) [NCBI Gene 7037] {aka CD71, IMD46, T9, TFR, TFR1, TR}, COX11 (cytochrome c oxidase copper chaperone COX11) [NCBI Gene 1353] {aka COX11P, MC4DN23}, CP (ceruloplasmin) [NCBI Gene 1356] {aka AB073614, CP-2}, HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091] {aka HIF-1-alpha, HIF-1A, HIF-1alpha, HIF1, HIF1-ALPHA, MOP1}, STEAP3 (STEAP3 metalloreductase) [NCBI Gene 55240] {aka AHMIO2, STMP3, TSAP6, dudlin-2, dudulin-2, pHyde}, MEMO1 (mediator of cell motility 1) [NCBI Gene 51072] {aka C2orf4, CGI-27, MEMO, NS5ATP7}, ATOX1 (antioxidant 1 copper chaperone) [NCBI Gene 475] {aka ATX1, HAH1} - **Diseases:** thalassemia (MESH:D013789), diarrhea (MESH:D003967), gastrointestinal upset (MESH:D005767), degenerative dermopathy (MESH:D019636), endometrial and ovarian cancer (MESH:D004714), taste disturbances (MESH:D013651), lead poisoning (MESH:D007855), colon carcinoma cancer (MESH:D015179), fibrosarcoma (MESH:D005354), neurological deterioration (MESH:D009422), melanoma (MESH:D008545), obese (MESH:D009765), gliosarcoma tumors (MESH:D018316), cytotoxic (MESH:D064420), hepatocellular carcinoma (MESH:D006528), death (MESH:D003643), multiple myeloma (MESH:D009101), GEMMs (MESH:D007942), prostate cancer (MESH:D011471), skin rashes (MESH:D005076), lung cancer (MESH:D008175), heart disease (MESH:D006331), lupus like (MESH:D008180), alcoholism (MESH:D000437), pancreatic cancer (MESH:D010190), carcinogenesis (MESH:D063646), metastases (MESH:D009362), Wilson disease (MESH:D006527), Cu poisoning (MESH:D011041), adenocarcinoma of mouse prostate (MESH:D000230), neuroblastoma (MESH:D009447), severe combined immunodeficient (MESH:D016511), glioblastoma multiforme (MESH:D005909), pancreatic neuroendocrine tumor (MESH:D018358), proteinuria (MESH:D011507), colon (MESH:D003108), leukemia (MESH:D007938), testicular cancer (MESH:D013736), inflammation (MESH:D007249), malignant lymphoma (MESH:D008223), diabetic (MESH:D003920), sideroblastic anemia (MESH:D000756), squamous cell carcinoma (MESH:D002294), malignant mesothelioma (MESH:D000086002), breast cancer (MESH:D001943), colon carcinoma (MESH:D003110), hemochromatosis (MESH:D006432), cervical cancer (MESH:D002583), copper dyshomeostasis (MESH:C535468), Rheumatoid arthritis (MESH:D001172), kidney cancer (MESH:D007680), neurological worsening (MESH:D000067251), cancer diseases (MESH:D009369), liver disease (MESH:D008107) - **Chemicals:** DFP (MESH:D007531), 8-hydroxyquinoline (MESH:D015125), Cu(I) (MESH:C073870), semicarbazone (MESH:D012664), Pt (MESH:D010984), Ca (MESH:D002118), Cu S (MESH:C017846), catechols (MESH:D002396), penicillin (MESH:D010406), CQ (MESH:C048021), PLGA (MESH:D000077182), ROS (MESH:D017382), BHT (MESH:D002084), molybdenum (MESH:D008982), gemcitabine (MESH:D000093542), Syprine (MESH:D014266), oligopeptide (MESH:D009842), lipid (MESH:D008055), boronic acid (MESH:D001897), disulfiram (MESH:D004221), PS (MESH:D010758), Lewis Acid (MESH:D058116), imidazole (MESH:C029899), Curcuminoid (MESH:D036381), dopamine (MESH:D004298), BLM (MESH:D001761), Deferiprone (MESH:D000077543), DFO (MESH:C000709069), vemurafenib (MESH:D000077484), Triapine (MESH:C078157), Cuprimine (MESH:D010396), Copper (MESH:D003300), disulfide (MESH:D004220), O (MESH:D010100), PEG (MESH:D011092), hydrazide (MESH:D006834), cysteine (MESH:D003545), drinking water (MESH:D060766), Propidium Iodide (MESH:D011419), Deferasirox (MESH:D000077588), melanin (MESH:D008543), water (MESH:D014867), PEG-b-PCL (MESH:C521904), PAA (MESH:D010463), PBS (MESH:D007854), ATP (MESH:D000255), superoxide anion (MESH:D013481), N (MESH:D009584), (TC1-S)2 (-), Curcumin (MESH:D003474), DpC (MESH:C000607942), heme (MESH:D006418), malondialdehyde (MESH:D008315), singlet oxygen (MESH:D026082), 5-chloro-8-hydroxyquinoline (MESH:C043669), TM (MESH:D013932), 8-hydroxylquinoline (MESH:C586937), 3-AP (MESH:C001355), glycopeptide (MESH:D006020), alpha-amino acid (MESH:D000596) - **Species:** Mus musculus (house mouse, species) [taxon 10090], Human papillomavirus 16 (serotype) [taxon 333760], Drosophila melanogaster (fruit fly, species) [taxon 7227], Bacteria Latreille et al. 1825 (Bacteria stick insect, genus) [taxon 629395], Streptomyces verticillus (species) [taxon 29309], Rattus norvegicus (brown rat, species) [taxon 10116], Homo sapiens (human, species) [taxon 9606], Saccharomyces cerevisiae (baker's yeast, species) [taxon 4932] - **Mutations:** V600 - **Cell lines:** A549 — Homo sapiens (Human), Lung adenocarcinoma, Cancer cell line (CVCL_0023), SW480 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0546), CHO — Cricetulus griseus (Chinese hamster), Spontaneously immortalized cell line (CVCL_0213), MCF-7 — Homo sapiens (Human), Invasive breast carcinoma of no special type, Cancer cell line (CVCL_0031), betaTC3 — Mus musculus (Mouse), Mouse insulinoma, Transformed cell line (CVCL_0172), MiaPaCa — Homo sapiens (Human), Pancreatic undifferentiated carcinoma, Cancer cell line (CVCL_0428), 4T1 — Mus musculus (Mouse), Malignant neoplasms of the mouse mammary gland, Cancer cell line (CVCL_0125), SMMC7721 — Homo sapiens (Human), Human papillomavirus-related endocervical adenocarcinoma, Cancer cell line (CVCL_0534), CL25 — Homo sapiens (Human), Lung adenocarcinoma, Cancer cell line (CVCL_N824), A375 — Homo sapiens (Human), Amelanotic melanoma, Cancer cell line (CVCL_0132), Jurkat — Homo sapiens (Human), Childhood T acute lymphoblastic leukemia, Cancer cell line (CVCL_0065), TRAMP — Mus musculus (Mouse), Carcinoma of the mouse prostate gland, Cancer cell line (CVCL_B459), MDA-MB-231 — Homo sapiens (Human), Breast adenocarcinoma, Cancer cell line (CVCL_0062), PC-3 — Homo sapiens (Human), Prostate carcinoma, Cancer cell line (CVCL_0035), 9L — Rattus norvegicus (Rat), Rat malignant glioma, Cancer cell line (CVCL_1928), U251 glioma — Homo sapiens (Human), Astrocytoma, Cancer cell line (CVCL_0021), CT26 — Mus musculus (Mouse), Mouse colon adenocarcinoma, Cancer cell line (CVCL_7254), HL-60 — Homo sapiens (Human), Adult acute myeloid leukemia with maturation, Cancer cell line (CVCL_0002), L1210 leukemia — Mus musculus (Mouse), Mouse leukemia, Cancer cell line (CVCL_0382), Caco-2 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0025) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC8078164/full.md ## Figures 11 figures with captions in the complete paper: https://tomesphere.com/paper/PMC8078164/full.md ## References 239 references — full list in the complete paper: https://tomesphere.com/paper/PMC8078164/full.md --- Source: https://tomesphere.com/paper/PMC8078164