Journal of Radiopharmaceuticals and Molecular Probes (대한방사성의약품학회지)

Korean Society of Radiopharmaceuticals and Molecular Probes (대한방사성의약품학회)
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Controversies in the Hypoxic Uptake Mechanism of Copper(II) diacetyl-di(N4-methylthiosemicarbazone): An Updated Review

  • Thuy Tien Nguyen (Department of Molecular Medicine, Brain Korea 21 four KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University) ;
  • Huu Bao Nguyen (Department of Molecular Medicine, Brain Korea 21 four KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University) ;
  • Min-Kyoung Kang (Non-Clinical Evaluation Center, KBIO Health) ;
  • Jeongsoo Yoo (Department of Molecular Medicine, Brain Korea 21 four KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University)
  • Received : 2023.12.13
  • Accepted : 2023.12.22
  • Published : 2023.12.30
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Abstract

Cu(II) diacetyl-di(N4-methylthiosemicarbazone), also known as Cu(II)-ATSM, is a popular copper-complexed thiosemicarbazone derivative that has been widely studied for hypoxia. [64Cu]Cu-ATSM has emerged as an effective tracer for positron emission tomography imaging to functionally characterize hypoxic tumors. However, understanding the precise mechanism of cellular uptake and metabolism of Cu(II)-ATSM remains a controversial task in which different hypotheses have been proposed. Herein, we will elucidate the current findings regarding the hypoxic uptake mechanism of Cu(II)-ATSM. Particularly, we will investigate the cell internalization mechanism and intracellular reduction of Cu(II)-ATSM.

Keywords

Acknowledgement

This work was supported by the R&D program of the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (No. RS-2023-00207942, and RS-2022-00197770). This research was also partially supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. HI22C1989).

References

  1. Barbara M, Pilar P, Feda A, Abdel KA. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia 2015;3:83-92.
  2. Jie Z, Tobias S, Steffen S, Bernhard B. Tumor hypoxia and cancer progression. Cancer Lett 2006;237:10-21.
  3. Bertrand CL. Effects of hypoxia on drug resistance phenotype and genotype in human glioma cell lines. J Neurooncol 1996;29:149-55.
  4. Nadine R, Thorsten C. Hypoxia-mediated drug resistance: Novel insights on the functional interaction of HIFs and cell death pathways. Drug Resist Updat 2011;14:191-201.
  5. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 2001;294(5545):1337-40.
  6. Kolstad P. Intercapillary distance, oxygen tension and local recurrence in cervix cancer. Scand J Clin Lab Invest Suppl 1968;106:145-57.
  7. Lise SM, Simon B, Marianne N, Lise B, Ole LM, Susanne K, Jens O. Identifying hypoxia in human tumors: A correlation study between 18F-FMISO PET and the Eppendorf oxygen-sensitive electrode. Acta Oncol 2010;49:934-40.
  8. Egesta L, Ilaria G, Arturo C, Cristina N, Gianfranco C, Luca T, Cristina F, Filippo L, Sandro Ma, Stefano F. PET radiopharmaceuticals for imaging of tumor hypoxia: a review of the evidence. Am J Nucl Mol Imaging 2014;4(4):365-84.
  9. Ryan CP, DaeHee K, Aaron WPM, Juan CC. Functional Imaging of Hypoxia: PET and MRI. Cancers 2023;15(13):3336-3357.
  10. Jerabek PA, Patrick TB, Kilbourn MR, Dischino DD, Welch MJ. Synthesis and biodistribution of 18F-labeled fluoronitroimidazoles: potential in vivo markers of hypoxic tissue. Int J Radiat Appl Instrum Part A 1986;37:599-605.
  11. Tateishi K, Sato M, Yamanaka S, Kanno H, Murata H, Inoue T, Kawahara N. Application of 62Cu-Diacetyl-Bis (N4-Methylthiosemicarbazone) PET Imaging to Predict Highly Malignant Tumor Grades and Hypoxia-Inducible Factor-1α Expression in Patients with Glioma. Am J Neuroradiol 2013;34(1):92-9.
  12. Minagawa Y, Shizukuishi K, Koike I, Horiuchi C, Watanuki K, Hata M, Omura M, Odagiri K, Tohnai I, Inoue T, Tateishi U. Assessment of tumor hypoxia by 62Cu-ATSM PET/CT as a predictor of response in head and neck cancer: A pilot study. Ann Nucl Med 2011;25: 339-45.
  13. Mathilde C, Sebastien G, Mathieu F, Aurelien V, Michel C, Francoise K, Caroline R, Mickael B. Focus on the controversial aspects of 64Cu-ATSM in tumoral hypoxia mapping by PET imaging. Front Med 2015;2:58.
  14. Fujibayashi Y, Taniuchi H, Yonekura Y, Ohtani H, Konishi J, Yokoyama A. Copper-62-ATSM: A new hypoxia imaging agent with high membrane permeability and low redox potential. J Nucl Med 1997;38:1155-60.
  15. Takahashi N, Fujibayashi Y, Yonekura Y, Welch MJ, Waki A, Tsuchida T, Sadato N, Sugimoto K, Itoh H. Evaluation of 62Cu labeled diacetyl-bis(N4-methylthiosemicarbazone) as a hypoxic tissue tracer in patients with lung cancer. J Nucl Med 2000;14(5):323-28.
  16. Fujibayashi Y, Cutler CS, Anderson CJ, McCarthy DW, Jones LA, Sharp T, Yonekura Y, Welch MJ. Comparative studies of Cu-64-ATSM and C-11-acetate in an acute myocardial infarction model: ex vivo imaging of hypoxia in rats. Nucl Med Biol 1999;26(1):117-21.
  17. Zornhagen KW, Hansen AE, Oxboel J, Clemmensen AE, Ali HHE, Kristensen AT, Kjaer A. Micro regional heterogeneity of 64Cu-ATSM and 18F-FDG uptake in canine soft tissue sarcomas: relation to cell proliferation, hypoxia and glycolysis. PLOS One 2015;10(10).
  18. Floberg JM, Wang L, Bandara N, Rashmi R, Mpoy C, Garbow JR, Rogers BE, Patti GJ, Schwarz JK. Alteration of Cellular Reduction Potential Will Change 64Cu-ATSM Signal With or Without Hypoxia. J Nucl Med 2020;61(3):427-32.
  19. Fantin J, Toutain J, Peres EA, Bernay B, Mehani SM, Helaine C, Bourgeois M, Brunaud C, Chazalviel L, Pontin J, Dulmont AC, Valable S, Cherel M, Bernaudin M. Assessment of hypoxia and oxidative-related changes in a lung-derived brain metastasis model by [64Cu][Cu(ATSM)] PET and proteomic studies. EJNMMI Res2023;13:102.
  20. Obata A, Yoshimi E, Waki A, Lewis JS, Oyama N, Welch MJ, Saji H, Yonekura Y, Fujibayashi Y. Retention mechanism of hypoxia selective nuclear imaging/radiotherapeutic agent cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) in tumor cells. Ann Nucl Med 2001;15(6):499-504.
  21. Hueting R, Kersemans V, Cornelissen B, Tredwell M, Hussien K, Christlieb M, Gee AD, Passchier J, Smart SC, Dilworth JR, Gouverneur V, Muschel RJ. A comparison of the behavior of 64Cu-acetate and 64Cu-ATSM in vitro and in vivo. J Nucl Med. 2014;55(1):128-34.
  22. Peres EA, Toutain J, Paty LP, Divoux D, Ibazizene M, Guillouet S, Barre L, Vidal A, Cherel M, Bourgeois M, Bernaudin M, Valable S. 64Cu-ATSM/64Cu-Cl2 and their relationship to hypoxia in glioblastoma: a preclinical study. EJNMMI Res 2019;9:114.
  23. Walke GR, Meron S, Shenberger Y, Airapetov LG, Ruthstein S. Cellular Uptake of the ATSM-Cu(II) Complex under Hypoxic Conditions. Chemistryopen 2021;10(4):486-92.
  24. Walke GR, Ruthstein S. Does the ATSM-Cu(II) Biomarker Intergrate into the Human Cellular Copper Cycle?. ACS Omega 2019;4:12278-85.
  25. Liu T, Karlsen M, Karlberg AM, Redalen KR. Hypoxia imaging and theranostic potential of [64Cu][Cu(ATSM)] and ionic Cu(II) salts: a review of current evidence and discussion of the retention mechanisms. EJNMMI Res 2020;10:33.