Strategies to combat cancer drug resistance: focus on copper metabolism and cuproptosis

Abstract

Cancer cells often develop tolerance to chemotherapy, targeted therapy, and immunotherapy drugs either before or during treatment. The significant heterogeneity among various tumors poses a critical challenge in modern cancer research, particularly in overcoming drug resistance. Copper, as an essential trace element in the body, participates in various biological processes of diseases, including cancers. The growth of many types of tumor cells exhibits a heightened dependence on copper. Thus, targeting copper metabolism or inducing cuproptosis may be potential ways to overcome cancer drug resistance. Copper chelators have shown potential in overcoming cancer drug resistance by targeting copper-dependent processes in cancer cells. In contrast, copper ionophores, copper-based nanomaterials, and other small molecules have been used to induce copper-dependent cell death (cuproptosis) in cancer cells, including drug-resistant tumor cells. This review summarizes the regulation of copper metabolism and cuproptosis in cancer cells and the role of copper metabolism and cuproptosis in cancer drug resistance, providing ideas for overcoming cancer resistance in the future.

Keywords

Cuproptosis / copper / metabolism / cell death / cancer / drug resistance

References

[1] Hanahan D.Hallmarks of cancer: new dimensions.Cancer Discov2022;12:31-46

[2] Szakács G,Ludwig JA,Gottesman MM.Targeting multidrug resistance in cancer.Nat Rev Drug Discov2006;5:219-34

[3] Parlani M,Friedl P.Plasticity of cancer invasion and energy metabolism.Trends Cell Biol2023;33:388-402 PMCID:PMC10368441

[4] Ban XX,Wan XX.Copper metabolism and cuproptosis: molecular mechanisms and therapeutic perspectives in neurodegenerative diseases.Curr Med Sci2024;44:28-50

[5] Díez M,Arroyo M.Use of the copper/zinc ratio in the diagnosis of lung cancer.Cancer1989;63:726-30

[6] Saleh SAK,Abdelkhaliq AA.Serum levels of selenium, zinc, copper, manganese, and iron in prostate cancer patients.Curr Urol2020;14:44-9 PMCID:PMC7206590

[7] Adeoti ML,Akanni EO,Oyeyemi GM.Trace elements; copper, zinc and selenium, in breast cancer afflicted female patients in LAUTECH Osogbo, Nigeria.Indian J Cancer2015;52:106-9

[8] Xue Q,Klionsky DJ,Liu J.Copper metabolism in cell death and autophagy.Autophagy2023;19:2175-95 PMCID:PMC10351475

[9] Tsang T,Gudiel AA,Feldser DM.Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma.Nat Cell Biol2020;22:412-24 PMCID:PMC7610258

[10] Brady DC,Turski ML.Copper is required for oncogenic BRAF signalling and tumorigenesis.Nature2014;509:492-6 PMCID:PMC4138975

[11] Guo J,Zheng N.Copper promotes tumorigenesis by activating the PDK1-AKT oncogenic pathway in a copper transporter 1 dependent manner.Adv Sci2021;8:e2004303 PMCID:PMC8456201

[12] Parke A,Palmer RM.Characterization and quantification of copper sulfate-induced vascularization of the rabbit cornea.Am J Pathol1988;130:173-8 PMCID:PMC1880543

[13] Lopez J,Vahdat L.12. Copper depletion as a therapeutic strategy in cancer. In: Essential metals in medicine: therapeutic use and toxicity of metal ions in the clinic. Berlin, Boston: De Gruyter, 2019; pp. 303-30.

[14] Kuo MT,Chou CY.Targeting the copper transport system to improve treatment efficacies of platinum-containing drugs in cancer chemotherapy.Pharmaceuticals2021;14:549 PMCID:PMC8227247

[15] Lukanović D,Kobal B.The contribution of copper efflux transporters ATP7A and ATP7B to chemoresistance and personalized medicine in ovarian cancer.Biomed Pharmacother2020;129:110401

[16] Petruzzelli R.Activity and trafficking of copper-transporting ATPases in tumor development and defense against platinum-based drugs.Cells2019;8:1080 PMCID:PMC6769697

[17] Tsvetkov P,Petrova B.Copper induces cell death by targeting lipoylated TCA cycle proteins.Science2022;375:1254-61 PMCID:PMC9273333

[18] Zhang C,Li L.Targeting cuproptosis for cancer therapy: mechanistic insights and clinical perspectives.J Hematol Oncol2024;17:68 PMCID:PMC11328505

[19] Gaetke LM.Copper toxicity, oxidative stress, and antioxidant nutrients.Toxicology2003;189:147-63

[20] Li Y,Wang R,Zheng S.Zinc transporter 1 functions in copper uptake and cuproptosis.Cell Metab2024;36:2118-29.e6

[21] Tang D,Kroemer G.Cuproptosis: a copper-triggered modality of mitochondrial cell death.Cell Res2022;32:417-8 PMCID:PMC9061796

[22] Attar N,Vogelauer M.The histone H3-H4 tetramer is a copper reductase enzyme.Science2020;369:59-64 PMCID:PMC7842201

[23] Grass G.CueO is a multi-copper oxidase that confers copper tolerance in Escherichia coli.Biochem Biophys Res Commun2001;286:902-8

[24] Kim JH,Lee J.Lysosomal SLC46A3 modulates hepatic cytosolic copper homeostasis.Nat Commun2021;12:290 PMCID:PMC7804329

[25] van den Berghe PV,Malingré HE.Human copper transporter 2 is localized in late endosomes and lysosomes and facilitates cellular copper uptake.Biochem J2007;407:49-59 PMCID:PMC2267400

[26] Qi Y,Li X,Zhang W.Cuproptosis-related gene SLC31A1: prognosis values and potential biological functions in cancer.Sci Rep2023;13:17790 PMCID:PMC10584849

[27] Holzer AK,Howell SB.Contribution of the major copper influx transporter CTR1 to the cellular accumulation of cisplatin, carboplatin, and oxaliplatin.Mol Pharmacol2006;70:1390-4

[28] Song IS,Siddik ZH.Role of human copper transporter Ctr1 in the transport of platinum-based antitumor agents in cisplatin-sensitive and cisplatin-resistant cells.Mol Cancer Ther2004;3:1543-9

[29] Lee YY,Do IG.Prognostic value of the copper transporters, CTR1 and CTR2, in patients with ovarian carcinoma receiving platinum-based chemotherapy.Gynecol Oncol2011;122:361-5

[30] Öhrvik H.The role of Ctr1 and Ctr2 in mammalian copper homeostasis and platinum-based chemotherapy.J Trace Elem Med Biol2015;31:178-82 PMCID:PMC4175275

[31] Yoshida H,Yamauchi M.Association of copper transporter expression with platinum resistance in epithelial ovarian cancer.Anticancer Res2013;33:1409-14

[32] Furukawa T,Ikeda R,Akiyama S.Copper transport systems are involved in multidrug resistance and drug transport.Curr Med Chem2008;15:3268-78

[33] Sturtz LA,Jensen LT,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 Chem2001;276:38084-9

[34] Wong PC,Subramaniam JR.Copper chaperone for superoxide dismutase is essential to activate mammalian Cu/Zn superoxide dismutase.Proc Natl Acad Sci U S A2000;97:2886-91 PMCID:PMC16025

[35] Feng W,Xue W,Kang YJ.Copper regulation of hypoxia-inducible factor-1 activity.Mol Pharmacol2009;75:174-82 PMCID:PMC2685058

[36] Li Y,Zhang X.Copper chaperone for superoxide dismutase promotes breast cancer cell proliferation and migration via ROS-mediated MAPK/ERK signaling.Front Pharmacol2019;10:356 PMCID:PMC6460305

[37] Wang J,Shan C.Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation.Nat Chem2015;7:968-79 PMCID:PMC4725056

[38] Garza NM,Maremanda KP,Gohil VM.Mitochondrial copper in human genetic disorders.Trends Endocrinol Metab2023;34:21-33 PMCID:PMC9780195

[39] Zhu SY,Niu YY.COX17 restricts renal fibrosis development by maintaining mitochondrial copper homeostasis and restoring complex IV activity.Acta Pharmacol Sin2023;44:2091-102 PMCID:PMC10545728

[40] Huang D,Ji Q.Lead aggravates Alzheimer’s disease pathology via mitochondrial copper accumulation regulated by COX17.Redox Biol2024;69:102990 PMCID:PMC10716782

[41] Suzuki C,Kikuchi T,Nakamura Y.Identification of COX17 as a therapeutic target for non-small cell lung cancer.Cancer Res2003;63:7038-41

[42] Yang D,Qiu B,Teng CB.Copper chaperone antioxidant 1: multiple roles and a potential therapeutic target.J Mol Med2023;101:527-42

[43] Maghool S,Roberts BR,Maher MJ.Human glutaredoxin-1 can transfer copper to isolated metal binding domains of the P_1B-type ATPase, ATP7B.Sci Rep2020;10:4157 PMCID:PMC7057996

[44] Mercer SW,Warr CG.Reduced glutathione biosynthesis in Drosophila melanogaster causes neuronal defects linked to copper deficiency.J Neurochem2016;137:360-70

[45] Itoh S,Nakagawa O.Novel role of antioxidant-1 (Atox1) as a copper-dependent transcription factor involved in cell proliferation.J Biol Chem2008;283:9157-67 PMCID:PMC2431038

[46] Dolgova NV,Yu CH,Dmitriev OY.Copper chaperone Atox1 interacts with the metal-binding domain of Wilson’s disease protein in cisplatin detoxification.Biochem J2013;454:147-56

[47] Palm-Espling ME,Björn E,Wittung-Stafshede P.Determinants for simultaneous binding of copper and platinum to human chaperone Atox1: hitchhiking not hijacking.PLoS One2013;8:e70473 PMCID:PMC3728025

[48] Karginova O,Raoul A.Inhibition of copper transport induces apoptosis in triple-negative breast cancer cells and suppresses tumor angiogenesis.Mol Cancer Ther2019;18:873-85

[49] Inkol JM,Mutsaers AJ.Inhibition of copper chaperones sensitizes human and canine osteosarcoma cells to carboplatin chemotherapy.Vet Comp Oncol2020;18:559-69

[50] Li YQ,Liu ZQ.Copper efflux transporters ATP7A and ATP7B: novel biomarkers for platinum drug resistance and targets for therapy.IUBMB Life2018;70:183-91

[51] Xue Q,Chen X.Copper-dependent autophagic degradation of GPX4 drives ferroptosis.Autophagy2023;19:1982-96 PMCID:PMC10283421

[52] Chen S,Koya K.Syntheses and antitumor activities of N’1,N’3-dialkyl-N’1,N’3-di-(alkylcarbonothioyl) malonohydrazide: the discovery of elesclomol.Bioorg Med Chem Lett2013;23:5070-6

[53] Tsvetkov P,Cai K.Mitochondrial metabolism promotes adaptation to proteotoxic stress.Nat Chem Biol2019;15:681-9 PMCID:PMC8183600

[54] Buccarelli M,Matarrese P.Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth.J Exp Clin Cancer Res2021;40:228 PMCID:PMC8273992

[55] Zheng P,Lu L,Ding Y.Elesclomol: a copper ionophore targeting mitochondrial metabolism for cancer therapy.J Exp Clin Cancer Res2022;41:271 PMCID:PMC9465867

[56] Zhang D,Wang F,Wang S.2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy.Cancer Lett2014;355:176-83

[57] Kluza J,Touil Y.Inactivation of the HIF-1α/PDK3 signaling axis drives melanoma toward mitochondrial oxidative metabolism and potentiates the therapeutic activity of pro-oxidants.Cancer Res2012;72:5035-47

[58] Gao J,Huang S,He W.Novel insights into anticancer mechanisms of elesclomol: More than a prooxidant drug.Redox Biol2023;67:102891 PMCID:PMC10518591

[59] Xu L,Li Y.Disulfiram: a Food and Drug Administration-approved multifunctional role in synergistically drug delivery systems for tumor treatment.Int J Pharm2022;626:122130

[60] Lu Y,Gao W.Leveraging disulfiram to treat cancer: mechanisms of action, delivery strategies, and treatment regimens.Biomaterials2022;281:121335

[61] Ding Y,Luo Y.A fibroblast activation protein α-activatable nanoagent co-delivering diethyldithiocarbamate and copper for tumor therapy and imaging.Acta Biomater2024;187:316-27

[62] Ren X,Zhou Y.Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis.Redox Biol2021;46:102122 PMCID:PMC8416961

[63] Zhang P,Ren X.Inhibiting the compensatory elevation of xCT collaborates with disulfiram/copper-induced GSH consumption for cascade ferroptosis and cuproptosis.Redox Biol2024;69:103007 PMCID:PMC10788306

[64] Chen D,Yang H.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 Res2006;66:10425-33

[65] Cater MA.Clioquinol induces cytoplasmic clearance of the X-linked inhibitor of apoptosis protein (XIAP): therapeutic indication for prostate cancer.Biochem J2011;436:481-91

[66] Cater MA,Wolyniec K.Increasing intracellular bioavailable copper selectively targets prostate cancer cells.ACS Chem Biol2013;8:1621-31

[67] Lu X,Lin C.Elesclomol loaded copper oxide nanoplatform triggers cuproptosis to enhance antitumor immunotherapy.Adv Sci2024;11:e2309984 PMCID:PMC11095170

[68] Zhang J,Zhang J.Syphilis mimetic nanoparticles for cuproptosis-based synergistic cancer therapy via reprogramming copper metabolism.Int J Pharm2023;640:123025

[69] Chang J,Zhi H.Copper deposition in polydopamine nanostructure to promote cuproptosis by catalytically inhibiting copper exporters of tumor cells for cancer immunotherapy.Small2024;20:e2308565

[70] Zhang N,Rao K.Biomimetic copper-doped polypyrrole nanoparticles induce glutamine metabolism inhibition to enhance breast cancer cuproptosis and immunotherapy.J Control Release2024;371:204-15

[71] Xu Y,Zeng L.An enzyme-engineered nonporous copper(I) coordination polymer nanoplatform for cuproptosis-based synergistic cancer therapy.Adv Mater2022;34:e2204733

[72] Du C,Qiu X.Self-reinforced bimetallic mito-jammer for Ca²⁺ overload-mediated cascade mitochondrial damage for cancer cuproptosis sensitization.Adv Sci2024;11:e2306031 PMCID:PMC11022715

[73] Li Y,Weichselbaum RR.Mitochondria-targeted multifunctional nanoparticles combine cuproptosis and programmed cell death-1 downregulation for cancer immunotherapy.Adv Sci2024;11:e2403520 PMCID:PMC11425249

[74] Huang H,Liu J.Dendrimer/metal-phenolic nanocomplexes encapsulating CuO₂ for targeted magnetic resonance imaging and enhanced ferroptosis/cuproptosis/chemodynamic therapy by regulating the tumor microenvironment.Acta Biomater2024;183:252-63

[75] Lu S,Li B.An ellagic acid coordinated copper-based nanoplatform for efficiently overcoming cancer chemoresistance by cuproptosis and synergistic inhibition of cancer cell stemness.Small2024;20:e2309215

[76] Lu Y,Gao W,He B.Reversal of cisplatin chemotherapy resistance by glutathione-resistant copper-based nanomedicine via cuproptosis.J Mater Chem B2022;10:6296-306

[77] Yang F,Zhou HC.Deep learning enables the discovery of a novel cuproptosis-inducing molecule for the inhibition of hepatocellular carcinoma.Acta Pharmacol Sin2024;45:391-404 PMCID:PMC10789809

[78] Wang W,Jiang X.Ferroptosis inducers enhanced cuproptosis induced by copper ionophores in primary liver cancer.J Exp Clin Cancer Res2023;42:142 PMCID:PMC10242978

[79] Huang Q,Zhang J.Eupalinolide B suppresses pancreatic cancer by ROS generation and potential cuproptosis.iScience2024;27:110496 PMCID:PMC11295471

[80] Yang X,Diao X.Targeting cuproptosis by zinc pyrithione in triple-negative breast cancer.iScience2023;26:108218 PMCID:PMC10637938

[81] Nie X,Xiong Y,Liu T.Anisomycin has a potential toxicity of promoting cuproptosis in human ovarian cancer stem cells by attenuating YY1/lipoic acid pathway activation.J Cancer2022;13:3503-14 PMCID:PMC9723990

[82] Yang Y,Geng H.Proteomics revealed the crosstalk between copper stress and cuproptosis, and explored the feasibility of curcumin as anticancer copper ionophore.Free Radic Biol Med2022;193:638-47

[83] Zhang W,Shi H.Curcumin is a biologically active copper chelator with antitumor activity.Phytomedicine2016;23:1-8

[84] Liu Z,Lai Z.The role of ferroptosis and cuproptosis in curcumin against hepatocellular carcinoma.Molecules2023;28:1623 PMCID:PMC9964324

[85] Sun L,Yang B.Lactylation of METTL16 promotes cuproptosis via m⁶A-modification on FDX1 mRNA in gastric cancer.Nat Commun2023;14:6523 PMCID:PMC10589265

[86] Katano K,Safaei R.Acquisition of resistance to cisplatin is accompanied by changes in the cellular pharmacology of copper.Cancer Res2002;62:6559-65

[87] Komatsu M,Mutoh M.Copper-transporting P-type adenosine triphosphatase (ATP7B) is associated with cisplatin resistance.Cancer Res2000;60:1312-6

[88] Samimi G,Wilczynski S,Alberts DS.Increase in expression of the copper transporter ATP7A during platinum drug-based treatment is associated with poor survival in ovarian cancer patients.Clin Cancer Res2003;9:5853-9

[89] Lin X,Holzer A.The copper transporter CTR1 regulates cisplatin uptake in Saccharomyces cerevisiae.Mol Pharmacol2002;62:1154-9

[90] Owatari S,Komatsu M.Copper-transporting P-type ATPase, ATP7A, confers multidrug resistance and its expression is related to resistance to SN-38 in clinical colon cancer.Cancer Res2007;67:4860-8

[91] Ishida S,Smith-McCune K.Enhancing tumor-specific uptake of the anticancer drug cisplatin with a copper chelator.Cancer Cell2010;17:574-83 PMCID:PMC2902369

[92] Zhang X,Su Y.AMPK phosphorylates and stabilises copper transporter 1 to synergise metformin and copper chelator for breast cancer therapy.Br J Cancer2023;128:1452-65 PMCID:PMC10070418

[93] Zhang W,Chen C.Curcumin enhances cisplatin sensitivity of human NSCLC cell lines through influencing Cu-Sp1-CTR1 regulatory loop.Phytomedicine2018;48:51-61

[94] Shi X,Jia M.A novel copper chelator for the suppression of colorectal cancer.Drug Dev Res2023;84:312-25

[95] Wangpaichitr M,You M.N’,N’-Dimethyl-N’,N’-bis(phenylcarbonothioyl) propanedihydrazide (Elesclomol) selectively kills cisplatin resistant lung cancer cells through reactive oxygen species (ROS).Cancers2009;1:23-38 PMCID:PMC2882109

[96] Cierlitza M,Bogeski I.Mitochondrial oxidative stress as a novel therapeutic target to overcome intrinsic drug resistance in melanoma cell subpopulations.Exp Dermatol2015;24:155-7 PMCID:PMC4335723

[97] Sun Y,Chen X,Luo B.Inhibition of mitochondrial respiration overcomes hepatocellular carcinoma chemoresistance.Biochem Biophys Res Commun2019;508:626-32

[98] Denise C,Calvani M.5-fluorouracil resistant colon cancer cells are addicted to OXPHOS to survive and enhance stem-like traits.Oncotarget2015;6:41706-21 PMCID:PMC4747183

[99] Corazao-Rozas P,Jendoubi M.Mitochondrial oxidative stress is the Achille’s heel of melanoma cells resistant to Braf-mutant inhibitor.Oncotarget2013;4:1986-98 PMCID:PMC3875764

[100] Monk BJ,Moxley KM.A phase II evaluation of elesclomol sodium and weekly paclitaxel in the treatment of recurrent or persistent platinum-resistant ovarian, fallopian tube or primary peritoneal cancer: an NRG oncology/gynecologic oncology group study.Gynecol Oncol2018;151:422-7 PMCID:PMC6392076

[101] O’Day SJ,Chiarion-Sileni V.Final results of phase III SYMMETRY study: randomized, double-blind trial of elesclomol plus paclitaxel versus paclitaxel alone as treatment for chemotherapy-naive patients with advanced melanoma.J Clin Oncol2013;31:1211-8

[102] Berkenblit A,Ryan DP.Phase I clinical trial of STA-4783 in combination with paclitaxel in patients with refractory solid tumors.Clin Cancer Res2007;13:584-90

[103] Liu P,Brown S.Disulfiram targets cancer stem-like cells and reverses resistance and cross-resistance in acquired paclitaxel-resistant triple-negative breast cancer cells.Br J Cancer2013;109:1876-85 PMCID:PMC3790184

[104] Yang Z,Albers AE,Kaufmann AM.Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines.Biomed Pharmacother2019;113:108727

[105] Guo X,Pandey S.Disulfiram/copper complex inhibiting NFkappaB activity and potentiating cytotoxic effect of gemcitabine on colon and breast cancer cell lines.Cancer Lett2010;290:104-13

[106] Wang W,Cassidy J.Disulfiram-mediated inhibition of NF-kappaB activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines.Int J Cancer2003;104:504-11

[107] Wang Y,Zhang J.Cuproptosis: a novel therapeutic target for overcoming cancer drug resistance.Drug Resist Updat2024;72:101018

[108] Wen H,Wang Z.Cuproptosis enhances docetaxel chemosensitivity by inhibiting autophagy via the DLAT/mTOR pathway in prostate cancer.FASEB J2023;37:e23145

[109] Gao X,Liu J.Enzalutamide sensitizes castration-resistant prostate cancer to copper-mediated cell death.Adv Sci2024;11:e2401396 PMCID:PMC11321675

[110] Li P,Bai S,Zhao L.Combination of the cuproptosis inducer disulfiram and anti‑PD‑L1 abolishes NSCLC resistance by ATP7B to regulate the HIF‑1 signaling pathway.Int J Mol Med2024;53:19 PMCID:PMC10781418

[111] Jin Y,Pan S.Baicalein enhances cisplatin sensitivity in cervical cancer cells by promoting cuproptosis through the Akt pathway.Biomed Pharmacother2024;179:117415

[112] Gao Y,Zhang P.Elesclomol-copper synergizes with imidazole ketone erastin by promoting cuproptosis and ferroptosis in myelodysplastic syndromes.Biomed Pharmacother2024;175:116727

[113] Liu Z,Lu K.The long noncoding RNA HOTAIR contributes to cisplatin resistance of human lung adenocarcinoma cells via downregualtion of p21(WAF1/CIP1) expression.PLoS One2013;8:e77293 PMCID:PMC3796503

[114] Raju GSR,Bandaru SS.HOTAIR: a potential metastatic, drug-resistant and prognostic regulator of breast cancer.Mol Cancer2023;22:65 PMCID:PMC10061914

[115] Wang J,Yang J.The long noncoding RNA H19 promotes tamoxifen resistance in breast cancer via autophagy.J Hematol Oncol2019;12:81 PMCID:PMC6657081

[116] Wei M,Luo Z,Wang J.Prognostic analysis of hepatocellular carcinoma based on cuproptosis -associated lncRNAs.BMC Gastroenterol2024;24:142 PMCID:PMC11040954

[117] Wang X,Shi H.MUC20 regulated by extrachromosomal circular DNA attenuates proteasome inhibitor resistance of multiple myeloma by modulating cuproptosis.J Exp Clin Cancer Res2024;43:68 PMCID:PMC10913264

[118] Quan B,Yao F.LINC02362/hsa-miR-18a-5p/FDX1 axis suppresses proliferation and drives cuproptosis and oxaliplatin sensitivity of hepatocellular carcinoma.Am J Cancer Res2023;13:5590-609 PMCID:PMC10695789

[119] Chen T,Zeng W.Down-regulation of long non-coding RNA HOTAIR sensitizes breast cancer to trastuzumab.Sci Rep2019;9:19881 PMCID:PMC6934784

[120] Li Z,Li J.Knockdown of lncRNA-HOTAIR downregulates the drug-resistance of breast cancer cells to doxorubicin via the PI3K/AKT/mTOR signaling pathway.Exp Ther Med2019;18:435-42 PMCID:PMC6580102

[121] Dong C,Xu W.The coppery age: copper (Cu)-involved nanotheranostics.Adv Sci2020;7:2001549 PMCID:PMC7610332

[122] Ferrari M.Cancer nanotechnology: opportunities and challenges.Nat Rev Cancer2005;5:161-71