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Abstract

Introduction

Copper complexes, as endogenous metals, have potential in cancer therapy, addressing issues associated with cisplatin. Since cisplatin uses Copper Transporter 1 (CTR1) for cellular entry, copper complexes may utilize this pathway to enhance transport efficiency.

Methods

The Cu/Na dipicolinic acid complex was synthesized to assess its cytotoxicity, induction of apoptosis, drug resistance, and inflammation in cancerous and normal lung cells. The effects of oxidative stress on erythrocytes were also examined.

Results

Cytotoxicity tests (MTT and SRB) showed superior inhibitory effects on A549 lung cancer cells compared to cisplatin, with no toxicity observed in MRC-5 normal lung fibroblast cells. Real-time PCR revealed increased caspase-3 expression (extrinsic apoptosis) for the complex compared to cisplatin, possibly due to CTR1-mediated entry. The complex did not induce drug resistance, as shown by AKT1 expression, and reduced TNF-α expression, preventing inflammation in normal cells. In contrast to cisplatin, the complex caused minimal oxidative stress in erythrocytes.

Discussion

It can be concluded that the Cu/Na dipicolinic acid complex may be easily transported by CTR1 to malignant tumors, particularly lung cancer. This complex has the ability to inhibit cancer cell growth and induce apoptosis in lung cancer cells. Therefore, copper complexes show promise as potential therapeutic options for treating this type of cancer.

Conclusion

The copper/sodium complex demonstrates enhanced therapeutic efficacy in lung cancer cells, requiring lower doses than cisplatin, while being safer for normal cells and erythrocytes.

© 2025 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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2025-09-03
2025-11-09

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References

  1. Pickart L. Margolina A. Regenerative and protective actions of the ghk-cu peptide in the light of the new gene data. Int. J. Mol. Sci. 2018 19 7 1987 10.3390/ijms19071987 29986520
    [Google Scholar]
  2. Bian Y. Deng M. Liu J. Li J. Zhang Q. Wang Z. Liao L. Miao J. Li R. Zhou X. Hou G. The glycyl-l-histidyl-l-lysine-Cu2+ tripeptide complex attenuates lung inflammation and fibrosis in silicosis by targeting peroxiredoxin 6. Redox Biol. 2024 75 103237 10.1016/j.redox.2024.103237 38879894
    [Google Scholar]
  3. Ma W. Li M. Ma H. Li W. Liu L. Yin Y. Zhou X. Hou G. Protective effects of GHK-Cu in bleomycin-induced pulmonary fibrosis via anti-oxidative stress and anti-inflammation pathways. Life Sci. 2020 241 117139 10.1016/j.lfs.2019.117139 31809714
    [Google Scholar]
  4. Abdullah M.F. Cinkilic N. Vatan O. Inci D. Aydin R. Antiproliferative effects of novel copper (II) complexes on lung cancer cell line. bioRxiv 2022
    [Google Scholar]
  5. Wang Y. Tang T. Yuan Y. Li N. Wang X. Guan J. Copper and copper complexes in tumor therapy. ChemMedChem 2024 19 11 202400060 10.1002/cmdc.202400060 38443744
    [Google Scholar]
  6. Arnesano F. Natile G. Interference between copper transport systems and platinum drugs. Semin. Cancer Biol. 2021 76 173 188 10.1016/j.semcancer.2021.05.023 34058339
    [Google Scholar]
  7. Kuo M.T. Huang Y.F. Chou C.Y. Chen H.H.W. Targeting the copper transport system to improve treatment efficacies of platinum-containing drugs in cancer chemotherapy. Pharmaceuticals 2021 14 6 549 10.3390/ph14060549 34201235
    [Google Scholar]
  8. Ji P. Wang P. Chen H. Xu Y. Ge J. Tian Z. Yan Z. Potential of copper and copper compounds for anticancer applications. Pharmaceuticals 2023 16 2 234 10.3390/ph16020234 37259382
    [Google Scholar]
  9. Gul N.S. Khan T.M. Chen M. Huang K.B. Hou C. Choudhary M.I. Liang H. Chen Z.F. New copper complexes inducing bimodal death through apoptosis and autophagy in A549 cancer cells. J. Inorg. Biochem. 2020 213 111260 10.1016/j.jinorgbio.2020.111260 33039746
    [Google Scholar]
  10. Heidari A. Dehghanian E. Razmara Z. Shahraki S. Samareh Delarami H. Heidari Majd M. Effect of Cu(II) compound containing dipicolinic acid on DNA damage: A study of antiproliferative activity and DNA interaction properties by spectroscopic, molecular docking and molecular dynamics approaches. J. Biomol. Struct. Dyn. 2024 ••• 1 16 10.1080/07391102.2024.2329308 38498382
    [Google Scholar]
  11. Yang R. Roshani D. Gao B. Li P. Shang N. Metallothionein: A comprehensive review of its classification, structure, biological functions, and applications. Antioxidants 2024 13 7 825 10.3390/antiox13070825 39061894
    [Google Scholar]
  12. Zhao R. Sukocheva O. Tse E. Neganova M. Aleksandrova Y. Zheng Y. Gu H. Zhao D. Madhunapantula S.V. Zhu X. Liu J. Fan R. Cuproptosis, the novel type of oxidation-induced cell death in thoracic cancers: Can it enhance the success of immunotherapy? Cell Commun. Signal. 2024 22 1 379 10.1186/s12964‑024‑01743‑2 39068453
    [Google Scholar]
  13. Ruiz L.M. Libedinsky A. Elorza A.A. Role of copper on mitochondrial function and metabolism. Front. Mol. Biosci. 2021 8 711227 10.3389/fmolb.2021.711227 34504870
    [Google Scholar]
  14. Kirillova M.V. Kirillov A.M. Guedes da Silva M.F.C. Pombeiro A.J.L. Self‐assembled two‐dimensional water‐soluble dipicolinate cu/na coordination polymer: Structural features and catalytic activity for the mild peroxidative oxidation of cycloalkanes in acid‐free medium. Eur. J. Inorg. Chem. 2008 2008 22 3423 3427 10.1002/ejic.200800355
    [Google Scholar]
  15. Sargazi A. Barani A. Heidari Majd M. Synthesis and apoptotic efficacy of biosynthesized silver nanoparticles using acacia luciana flower extract in MCF-7 breast cancer cells: Activation of bak1 and bclx for cancer therapy. Bionanoscience 2020 10 3 683 689 10.1007/s12668‑020‑00753‑x
    [Google Scholar]
  16. Orellana E. Kasinski A. Sulforhodamine B. Sulforhodamine B. SRB) assay in cell culture to investigate cell proliferation. Bio Protoc. 2016 6 21 1984 10.21769/BioProtoc.1984 28573164
    [Google Scholar]
  17. Dou J. Mi Y. Daneshmand S. Heidari Majd M. The effect of magnetic nanoparticles containing hyaluronic acid and methotrexate on the expression of genes involved in apoptosis and metastasis in A549 lung cancer cell lines. Arab. J. Chem. 2022 15 12 104307 10.1016/j.arabjc.2022.104307
    [Google Scholar]
  18. Zhang X. Heidari Majd M. Synthesis of halloysite nanotubes decorated with green silver nanoparticles to investigate cytotoxicity, lipid peroxidation and induction of apoptosis in acute leukemia cells. Sci. Rep. 2023 13 1 17182 10.1038/s41598‑023‑43978‑y 37821481
    [Google Scholar]
  19. Kumar Sahoo P. Kumar Biswal S. Azam M. Transition metal complexes produced from dipicolinic acid: Synthesis, structural characterization, and anti-microbial investigations. Bull. Chem. Soc. Ethiop. 2022 36 3 607 615 10.4314/bcse.v36i3.10
    [Google Scholar]
  20. Choroba K. Filipe B. Świtlicka A. Penkala M. Machura B. Bieńko A. Cordeiro S. Baptista P.V. Fernandes A.R. In Vitro and In Vivo biological activities of dipicolinate oxovanadium(IV) complexes. J. Med. Chem. 2023 66 13 8580 8599 10.1021/acs.jmedchem.3c00255 37311060
    [Google Scholar]
  21. Li C. Li Y. Ding C. The role of copper homeostasis at the host-pathogen axis: From bacteria to fungi. Int. J. Mol. Sci. 2019 20 1 175 10.3390/ijms20010175 30621285
    [Google Scholar]
  22. Cobine P.A. Brady D.C. Cuproptosis: Cellular and molecular mechanisms underlying copper-induced cell death. Mol. Cell 2022 82 10 1786 1787 10.1016/j.molcel.2022.05.001 35594843
    [Google Scholar]
  23. Guo J. Cheng J. Zheng N. Zhang X. Dai X. Zhang L. Hu C. Wu X. Jiang Q. Wu D. Okada H. Pandolfi P.P. Wei W. Copper promotes tumorigenesis by activating the PDK1‐AKT oncogenic pathway in a copper transporter 1 dependent manner. Adv. Sci. 2021 8 18 2004303 10.1002/advs.202004303 34278744
    [Google Scholar]
  24. Heuberger D.M. Wolint P. Jang J.H. Itani S. Jungraithmayr W. Waschkies C.F. Meier-Bürgisser G. Andreoli S. Spanaus K. Schuepbach R.A. Calcagni M. Fahrni C.J. Buschmann J. High-Affinity Cu(I)-chelator with potential anti-tumorigenic action—a proof-of-principle experimental study of human H460 tumors in the cam assay. Cancers 2022 14 20 5122 10.3390/cancers14205122 36291910
    [Google Scholar]
  25. Gaun S. Ali S.A. Singh P. Patwa J. Flora S.J.S. Datusalia A.K. Melatonin ameliorates chronic copper-induced lung injury. Environ. Sci. Pollut. Res. Int. 2022 30 10 24949 24962 10.1007/s11356‑022‑19930‑4 35359208
    [Google Scholar]
  26. Abdolmaleki S. Aliabadi A. Khaksar S. Unveiling the promising anticancer effect of copper-based compounds: A comprehensive review. J. Cancer Res. Clin. Oncol. 2024 150 4 213 10.1007/s00432‑024‑05641‑5 38662225
    [Google Scholar]
  27. Heidari A. Mansouri-Torshizi H. Saeidifar M. Dehghanian E. Abdi K. Delarami H.S. Diverse coordination of dipicolinic acid to Pd(II) ion result antitumor complexes, their interaction with CT-DNA by spectroscopic experiments and computational methods. J. Mol. Struct. 2022 1261 132937 10.1016/j.molstruc.2022.132937
    [Google Scholar]
  28. Rai Y. Pathak R. Kumari N. Sah D.K. Pandey S. Kalra N. Soni R. Dwarakanath B.S. Bhatt A.N. Mitochondrial biogenesis and metabolic hyperactivation limits the application of MTT assay in the estimation of radiation induced growth inhibition. Sci. Rep. 2018 8 1 1531 10.1038/s41598‑018‑19930‑w 29367754
    [Google Scholar]
  29. Stepanenko A.A. Dmitrenko V.V. Pitfalls of the MTT assay: Direct and off-target effects of inhibitors can result in over/underestimation of cell viability. Gene 2015 574 2 193 203 10.1016/j.gene.2015.08.009 26260013
    [Google Scholar]
  30. He Y. Zhu Q. Chen M. Huang Q. Wang W. Li Q. Huang Y. Di W. The changing 50% inhibitory concentration (IC50) of cisplatin: A pilot study on the artifacts of the MTT assay and the precise measurement of density-dependent chemoresistance in ovarian cancer. Oncotarget 2016 7 43 70803 70821 10.18632/oncotarget.12223 27683123
    [Google Scholar]
  31. Guan D. Zhao L. Shi X. Ma X. Chen Z. Copper in cancer: From pathogenesis to therapy. Biomed. Pharmacother. 2023 163 114791 10.1016/j.biopha.2023.114791 37105071
    [Google Scholar]
  32. Schoeberl A. Gutmann M. Theiner S. Corte-Rodríguez M. Braun G. Vician P. Berger W. Koellensperger G. The copper transporter CTR1 and cisplatin accumulation at the single-cell level by LA-ICP-TOFMS. Front. Mol. Biosci. 2022 9 1055356 10.3389/fmolb.2022.1055356 36518851
    [Google Scholar]
  33. Akbarian M. Bertassoni L.E. Tayebi L. Biological aspects in controlling angiogenesis: Current progress. Cell. Mol. Life Sci. 2022 79 7 349 10.1007/s00018‑022‑04348‑5 35672585
    [Google Scholar]
  34. Tsvetkov P. Coy S. Petrova B. Dreishpoon M. Verma A. Abdusamad M. Rossen J. Joesch-Cohen L. Humeidi R. Spangler R.D. Eaton J.K. Frenkel E. Kocak M. Corsello S.M. Lutsenko S. Kanarek N. Santagata S. Golub T.R. Copper induces cell death by targeting lipoylated TCA cycle proteins. Science 2022 375 6586 1254 1261 10.1126/science.abf0529 35298263
    [Google Scholar]
  35. Magrì A. Tabbì G. Naletova I. Attanasio F. Arena G. Rizzarelli E. A deeper insight in metal binding to the hctr1 n-terminus fragment: Affinity, speciation and binding mode of binuclear Cu2+ and mononuclear Ag+ complex species. Int. J. Mol. Sci. 2022 23 6 2929 10.3390/ijms23062929 35328348
    [Google Scholar]
  36. Wang Y. Zhang L. Zhou F. Cuproptosis: A new form of programmed cell death. Cell. Mol. Immunol. 2022 19 8 867 868 10.1038/s41423‑022‑00866‑1 35459854
    [Google Scholar]
  37. Sheehan C. Muir A. The requirement for mitochondrial respiration in cancer varies with disease stage. PLoS Biol. 2022 20 9 3001800 10.1371/journal.pbio.3001800 36149877
    [Google Scholar]
  38. Mustafa M. Ahmad R. Tantry I.Q. Ahmad W. Siddiqui S. Alam M. Abbas K. Moinuddin; Hassan, M.I.; Habib, S.; Islam, S. Apoptosis: A comprehensive overview of signaling pathways, morphological changes, and physiological significance and therapeutic implications. Cells 2024 13 22 1838 10.3390/cells13221838 39594587
    [Google Scholar]
  39. Wang X. Lou Q. Fan T. Zhang Q. Yang X. Liu H. Fan R. Copper transporter Ctr1 contributes to enhancement of the sensitivity of cisplatin in esophageal squamous cell carcinoma. Transl. Oncol. 2023 29 101626 10.1016/j.tranon.2023.101626 36689863
    [Google Scholar]
  40. Kilari D. Guancial E. Kim E.S. Role of copper transporters in platinum resistance. World J. Clin. Oncol. 2016 7 1 106 113 10.5306/wjco.v7.i1.106 26862494
    [Google Scholar]
  41. Qian J. Zou Y. Rahman J.S.M. Lu B. Massion P.P. Synergy between phosphatidylinositol 3-kinase/Akt pathway and Bcl-xL in the control of apoptosis in adenocarcinoma cells of the lung. Mol. Cancer Ther. 2009 8 1 101 109 10.1158/1535‑7163.MCT‑08‑0973 19139118
    [Google Scholar]
  42. Liu L.Z. Zhou X.D. Qian G. Shi X. Fang J. Jiang B.H. AKT1 amplification regulates cisplatin resistance in human lung cancer cells through the mammalian target of rapamycin/p70S6K1 pathway. Cancer Res. 2007 67 13 6325 6332 10.1158/0008‑5472.CAN‑06‑4261 17616691
    [Google Scholar]
  43. Gao L. Zhang A. Copper-instigated modulatory cell mortality mechanisms and progress in oncological treatment investigations. Front. Immunol. 2023 14 1236063 10.3389/fimmu.2023.1236063 37600774
    [Google Scholar]
  44. Kunutsor S.K. Voutilainen A. Laukkanen J.A. Serum copper-to-zinc ratio and risk of chronic obstructive pulmonary disease: A cohort study. Lung 2023 201 1 79 84 10.1007/s00408‑022‑00591‑6 36464735
    [Google Scholar]
  45. Rock E. Mazur A. O’connor J.M. Bonham M.P. Rayssiguier Y. Strain J.J. The effect of copper supplementation on red blood cell oxidizability and plasma antioxidants in middle-aged healthy volunteers. Free Radic. Biol. Med. 2000 28 3 324 329 10.1016/S0891‑5849(99)00241‑5 10699742
    [Google Scholar]
  46. An Y. Li S. Huang X. Chen X. Shan H. Zhang M. The role of copper homeostasis in brain disease. Int. J. Mol. Sci. 2022 23 22 13850 10.3390/ijms232213850 36430330
    [Google Scholar]
  47. Altobelli G.G. Van Noorden S. Balato A. Cimini V. Copper/zinc superoxide dismutase in human skin: Current knowledge. Front. Med. 2020 7 183 10.3389/fmed.2020.00183 32478084
    [Google Scholar]
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Unveiling the Distinct Effects of a Two-Dimensional Copper/Sodium Complex: Oxidative Stress on Erythrocytes and Cytotoxicity, Apoptosis, Drug Resistance, and Inflammation in Lung Cancer Cells
Bentham Science Publishers ; https://doi.org/10.2174/0118715206380073250811113008
/content/journals/acamc/10.2174/0118715206380073250811113008
/content/journals/acamc/10.2174/0118715206380073250811113008
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  • Article Type:     Research Article
Keywords: AKT1 ; CTR1 ; TNF-α ; Apoptosis ; Bak1 ; metal complex

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