AccScience Publishing / ARNM / Online First / DOI: 10.36922/arnm.2822
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ORIGINAL RESEARCH ARTICLE

Evaluation of multidrug resistance in tumors using 99mTc-doxorubicin

Bianca Gutfilen1* ,  Sergio Augusto Lopes de Souza1 ,  Thiago Barboza1 ,  Bruna Fortunato Novis2 ,  Claudia Lopes Rodrigues Chagas1 ,  Maria Verônica Fonseca Torres de Oliveira1 ,  Vivian M. Rumjanek2
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1 Laboratory of Labeling Cells and Molecules, Department of Radiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
2 Institute of Medical Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
ARNM 2024, 2(1), 2822 https://doi.org/10.36922/arnm.2822
Submitted: 25 January 2024 | Accepted: 28 March 2024 | Published: 3 April 2024
© 2024 by the Author (s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Doxorubicin (DOX) is a potent chemotherapeutic agent used as the first-choice drug in treating different types of cancer, such as leukemia, lymphoma, and breast cancer, among others. However, the development of multidrug resistance represents a significant obstacle to the successful treatment of tumors. In this study, we assessed whether labeled DOX could be uptaken by susceptible and multidrug-resistant cell lines and by tumors in vivo in animals. The efficiency of DOX labeling was maintained at around 90% in this work. To evaluate the effect of 99mTc-DOX on cells expressing active P-glycoprotein (Pgp), we utilized cultured human chronic myeloid leukemia K562 cells and the resistant counterpart Lucena 1 cells. Lucena 1 cell line showed overexpression of Pgp that was not observed in K562. Our results suggested that the resistance to labeled or unlabeled DOX can be reversed by Pgp inhibition and can be easily detected. In conclusion, administering 99mTc-DOX into mice enables the differentiation between multidrug-resistant tumors in a non-invasive way and the evaluation of tumor resistance and possible chemosensitizers.

Keywords
Doxorubicin
Multidrug resistance
Tc-99m
99mTc-Doxorubicin
Funding
This study was supported by grants from Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
Conflict of interest
The authors declare they have no competing interests.
References
  1. Dickey JS, Rao VA. Current and proposed biomarkers of anthracycline cardiotoxicity in cancer: Emerging opportunities in oxidative damage and autophagy. Curr Mol Med. 2012;12(6):763-771. doi: 10.2174/156652412800792561

 

  1. Speth PA, van Hoesel QG, Haanen C. Clinical pharmacokinetics of doxorubicin. Clin Pharmacokinet. 1988;15(1):15-31. doi: 10.2165/00003088-198815010-00002

 

  1. Alkreathy HM, Damanhouri ZA, Ahmed N, Slevin M, Osman AMM. Mechanisms of cardioprotective effect of aged garlic extract against doxorubicin-induced cardiotoxicity. Integr Cancer Ther. 2012;11(4):364-370. doi: 10.1177/1534735411426726

 

  1. Rumjanek VM, Trindade GS, Wagner-Souza K, et al. Multidrug resistance in tumour cells: Characterisation of the multidrug resistant cell line K562-Lucena 1. An Acad Bras Ciênc. 2001;73(1):57-69. doi: 10.1590/s0001-37652001000100007

 

  1. Bernardo AA, Pinto-Silva FE, Persechini PM, et al. Effect of extracellular ATP on the human leukaemic cell line K562 and its multidrug counterpart. Mol Cell Biochem. 2006;289(1-2):111-124. doi: 10.1007/s11010-006-9154-2

 

  1. de Souza Votto AP, Renon VP, Yunes JS, et al. Sensitivity to microcystins: A comparative study in human cell lines with and without multidrug resistance phenotype. Cell Biol Int. 2007;31(11):1359-1366. doi: 10.1016/j.cellbi.2007.05.010

 

  1. Leite D, Kassuya C, Mazzuco T, et al. The cytotoxic effect and the multidrug resistance reversing action of lignans from Phyllanthus amarus. Planta Med. 2006;72(15): 1353-1358. doi: 10.1055/s-2006-951708

 

  1. Maia RC, Silva EA, Harab RC, Lucena M, Pires V, Rumjanek VM. Sensitivity of vincristine-sensitive K562 and vincristine-resistant K562-Lucena 1 cells to anthracyclines and reversal of multidrug resistance. Braz J Med Biol Res. 1996;29(4):467-472.

 

  1. Maia RC, Vasconcelos FC, de Sá Bacelar T, et al. LQB- 118, a pterocarpanquinone structurally related to lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone]: A novel class of agent with high apoptotic effect in chronic myeloid leukemia cells. Invest New Drugs. 2011;29(6): 1143-1155. doi: 10.1007/s10637-010-9453-z

 

  1. Netto CD, Santos ESJ, Castro CP, da Silva AJM, Rumjanek VM, Costa PRR. (±)-3,4-Dihydroxy-8,9-methylenedioxypterocarpan and derivatives: Cytotoxic effect on human leukemia cell lines. Eur J Med Chem. 2009;44(2):920-925. doi: 10.1016/j.ejmech.2008.01.027

 

  1. Salustiano EJS, Netto CD, Fernandes RF, et al. Comparison of the cytotoxic effect of lapachol, α-lapachone and pentacyclic 1,4-naphthoquinones on human leukemic cells. Invest New Drugs. 2010;28(2):139-144. doi: 10.1007/s10637-009-9231-y

 

  1. Votto APS, Domingues BS, Souza MMD, et al. Toxicity mechanisms of onion (Allium cepa) extracts and compounds in multidrug resistant erythroleukemic cell line. Water. 2010;43:429-437.

 

  1. Wagner-Souza K, Echevarria-Lima J, Rodrigues LAP, Reis M, Rumjanek VM. Resistance to thapsigargin-induced intracellular calcium mobilization in a multidrug resistant tumour cell line. Mol Cell Biochem. 2003;252(1-2):109-116. doi: 10.1023/a:1025586225941

 

  1. Brock I, Hipfner DR, Nielsen BS, et al. Sequential coexpression of the multidrug resistance genes MRP and mdr1 and their products in VP-16 (etoposide)-selected H69 small cell lung cancer cells. Cancer Res. 1995;55(3):459-462.

 

  1. Liu Z, Stevenson GD, Barrett HH, et al. Imaging recognition of inhibition of multidrug resistance in human breast cancer xenografts using 99mTc-labeled sestamibi and tetrofosmin. Nucl Med Biol. 2005;32(6):573-583. doi: 10.1016/j.nucmedbio.2005.04.014

 

  1. Tanaka PY, Calore EE. P-glycoprotein expression in non- Hodgkin’s lymphomas of human immunodeficiency virus infected patients. Pathol Res Pract. 2007;203(1):1-7. doi: 10.1016/j.prp.2006.09.004

 

  1. Crow MJ, Grant G, Provenzale JM, Wax A. Molecular imaging and quantitative measurement of epidermal growth factor receptor expression in live cancer cells using immunolabeled gold nanoparticles. Am J Roentgenol. 2009;192(4):1021-1028. doi: 10.2214/AJR.07.3535

 

  1. Dizdarevic S, Peters AM. Imaging of multidrug resistance in cancer. Cancer Imaging. 2011;11(1):1-8. doi: 10.1102/1470-7330.2011.0001

 

  1. Chhikara BS, Mandal D, Parang K. Synthesis. Anticancer activities, and cellular uptake studies of lipophilic derivatives of doxorubicin succinate. J Med Chem. 2012;55(4): 1500-1510. doi: 10.1021/jm201653u

 

  1. Lammers T, Storm G, Kiessling F. Nanomedicine formulations for combination therapies. Nano Rev. 2010; 1:1-3. doi: 10.3402/nano.v1i0.5705

 

  1. Lammers T, Hennink WE, Storm G. Tumour-targeted nanomedicines: Principles and practice. Br J Cancer. 2008;99(3):392-397. doi: 10.1038/sj.bjc.6604483

 

  1. Kaminskas LM, McLeod VM, Kelly BD, et al. Doxorubicin-conjugated PEGylated dendrimers show similar tumoricidal activity but lower systemic toxicity when compared to PEGylated liposome and solution formulations in mouse and rat tumor models. Mol Pharm. 2012;9(3):422-432. doi: 10.1021/mp200522d

 

  1. Gutfilen B, Rossini A, Martins FP, da Fonseca LM. Tc-99m-leukocytes--is it an intracellular labelling? J Clin Lab Immunol. 1999;51(1):1-7.

 

  1. Gutfilen B, Lopes de Souza SA, Martins FPP, Cardoso LR, Pinheiro Pessoa MC, Fonseca LMB. Use of 99mTc-mononuclear leukocyte scintigraphy in nosocomial fever. Acta Radiol. 2006;47(7):699-704. doi: 10.1080/02841850600791526

 

  1. Gutfilen B, Rodrigues E, Soraggi R, Barbosa Da Fonseca LH. Preliminary observation of 99mTc-thymine imaging in breast neoplasms. Nucl Med Commun. 2001;22(10): 1133-1137. doi: 10.1097/00006231-200110000-00013

 

  1. Lopes FPPL, de Azevedo MNL, Marchiori E, da Fonseca LMB, de Souza SAL, Gutfilen B. Use of 99mTc-anti-CD3 scintigraphy in the differential diagnosis of rheumatic diseases. Rheumatology. 2010;49(5):933-939. doi: 10.1093/rheumatology/kep471

 

  1. Roimicher L, Lopes FPPL, de Souza SL, et al. (99m)Tc-anti- TNF-α scintigraphy in RA: A comparison pilot study with MRI and clinical examination. Rheumatology (Oxford). 2011;50(11):2044-2050. doi: 10.1093/rheumatology/ker234

 

  1. Lopes FPPL, de Souza SAL, dos Santos Teixeira PF, et al. 99mTc-Anti-TNF-α scintigraphy: A new perspective within different methods in the diagnostic approach of active graves ophthalmopathy. Clin Nucl Med. 2012;37(11):1097-1101. doi: 10.1097/RLU.0b013e31826c0c16

 

  1. Rebelo Pinto ES, Lopes F, de Souza S, et al. A pilot study evaluating 99mTc-anti-TNF-alpha scintigraphy in Graves’ ophtalmopathy patients with different clinical activity score. Horm Metab Res. 2013;45(10):765-768. doi: 10.1055/s-0033-1349891

 

  1. Ribeiro MP, Souza SAL, Lopes FPPL, Rosado-de-Castro PH, Fonseca LMB, Gutfilen B. 99mTc-thymine scintigraphy may be a promising method in the diagnosis of breast cancer. Clinics (Sao Paulo). 2013;68(3):283-289. doi: 10.6061/clinics/2013(03)oa01

 

  1. de Souza S, Nentzinsky V, do Carmo C, Roimicher L, da Fonseca L, Gutfilen B. Scintigraphy for detecting tumour necrosis factor-α on the skin of patients with psoriatic arthritis. Scand J Rheumatol. 2017;46(5):377-380. doi: 10.1080/03009742.2016.1264627

 

  1. Silva JD, Lopes-Pacheco M, de Castro LL, et al. Eicosapentaenoic acid potentiates the therapeutic effects of adipose tissue-derived mesenchymal stromal cells on lung and distal organ injury in experimental sepsis. Stem Cell Res Ther. 2019;10(1):264. doi: 10.1186/s13287-019-1365-z

 

  1. Aguiar FS, Melo AS, Araújo AMS, et al. Autologous bone marrow-derived mononuclear cell therapy in three patients with severe asthma. Stem Cell Res Ther. 2020;11(1):167. doi: 10.1186/s13287-020-01675-x

 

  1. Gutfilen B, Pellini MP, de Roure e Neder J, et al. 99mTc labeling white blood cells with a simple technique: Clinical application. Ann Nucl Med. 1994;8(1):85-89. doi: 10.1007/BF03164991

 

  1. Lopes de Souza SA, Barbosa da Fonseca LM, Torres Gonçalves R, et al. Diagnosis of renal allograft rejection and acute tubular necrosis by 99mTc-mononuclear leukocyte imaging. Transplant Proc. 2004;36(10):2997-3001. doi: 10.1016/j.transproceed.2004.11.100

 

  1. Couto BG, Goldenberg RCS, da Fonseca LMB, et al. Bone marrow mononuclear cell therapy for patients with cirrhosis: A Phase 1 study. Liver Int. 2011;31(3):391-400. doi: 10.1111/j.1478-3231.2010.02424.x

 

  1. Carvalho AB, Quintanilha LF, Dias JV, et al. Bone marrow multipotent mesenchymal stromal cells do not reduce fibrosis or improve function in a rat model of severe chronic liver injury. Stem Cells. 2008;26(5):1307-1314. doi: 10.1634/stemcells.2007-0941

 

  1. Battistella V, de Freitas GR, da Fonseca LMB, et al. Safety of autologous bone marrow mononuclear cell transplantation in patients with nonacute ischemic stroke. Regen Med. 2011;6(1):45-52. doi: 10.2217/rme.10.97

 

  1. Barbosa da Fonseca LM, Gutfilen B, Rosado de Castro PH, et al. Migration and homing of bone-marrow mononuclear cells in chronic ischemic stroke after intra-arterial injection. Exp Neurol. 2010;221(1):122-128. doi: 10.1016/j.expneurol.2009.10.010

 

  1. Araujo FI, Proença FPP, Ferreira CG, et al. Use of 99]m Tc-doxorubicin scintigraphy in females with breast cancer: A pilot study. Br J Radiol. 2015;88(1052):20150268. doi: 10.1259/bjr.20150268

 

  1. Muzzammil T, Moore MJ, Hedley D, Ballinger JR. Comparison of (99m)Tc-sestamibi and doxorubicin to monitor inhibition of P-glycoprotein function. Br J Cancer. 2001;84(3):367-373. doi: 10.1054/bjoc.2000.1621

 

  1. Ohtani H, Ikegawa T, Honda Y, et al. Effects of various methoxyflavones on vincristine uptake and multidrug resistance to vincristine in P-gp-overexpressing K562/ADM cells. Pharm Res. 2007;24(10):1936-1943. doi: 10.1007/s11095-007-9320-6

 

  1. Mezi S, Primi F, Capoccetti F, Scopinaro F, Modesti M, Schillaci O. In vivo detection of resistance to anthracycline based neoadjuvant chemotherapy in locally advanced and inflammatory breast cancer with technetium-99m sestamibi scintimammography. Int J Oncol. 2003;22(6):1233-1240.

 

  1. Kostakoglu L. Noninvasive detection of multidrug resistance in patients with hematological malignancies: Are we there yet? Clin Lymphoma. 2002;2(4):242-248. doi: 10.3816/clm.2002.n.006

 

  1. Solbach C, Patt M, Reimold M, et al. [11C]Vinblastine syntheses and preliminary imaging in cancer patients. J Pharm Pharm Sci. 2007;10(2):266s-76s.

 

  1. Kurdziel KA, Kiesewetter DO. PET imaging of multidrug resistance in tumors using 18F-fluoropaclitaxel. Curr Top Med Chem. 2010;10(17):1792-1798. doi: 10.2174/156802610792928077

 

  1. Fornari FA, Randolph JK, Yalowich JC, Ritke MK, Gewirtz DA. Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells. Mol Pharmacol. 1994;45(4): 649-656.

 

  1. Momparler RL, Karon M, Siegel SE, Avila F. Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. Cancer Res. 1976;36(8):2891-2895.

 

  1. Polyak A, Palade EA, Balogh L, et al. In vitro and biodistribution examinations of Tc-99m-labelled doxorubicin-loaded nanoparticles. Nucl Med Rev Cent East Eur. 2011;14(2):55-62. doi: 10.5603/nmr.2011.00016

 

  1. Bao A, Goins B, Klipper R, Negrete G, Phillips WT. Direct 99m Tc labeling of pegylated liposomal doxorubicin (Doxil) for pharmacokinetic and non-invasive imaging studies. Pharmacology. 2004;308(2):419-425. doi: 10.1124/jpet.103.059535

 

  1. Sun H, Sloan A, Mangner TJ, et al. Imaging DNA synthesis with [18F]FMAU and positron emission tomography in patients with cancer. Eur J Nucl Med Mol Imaging. 2005;32(1):15-22. doi: 10.1007/s00259-004-1713-8

 

  1. Koukourakis MI, Koukouraki S, Fezoulidis I, et al. High intratumoural accumulation of stealth® liposomal doxorubicin (Caelyx®) in glioblastomas and in metastatic brain tumours. Br J Cancer. 2000;83(10):1281-1286. doi: 10.1054/bjoc.2000.1459

 

  1. Kumar P, Singh B, Sharma S, et al. Preclinical evaluation of [99m]Tc-Labeled doxorubicin as a potential scintigraphic probe for tumor imaging. Cancer Biother Radiopharm. 2012;27(3):221-225. doi: 10.1089/cbr.2011.1086

 

  1. Yang FY, Wang HE, Liu RS, et al. Pharmacokinetic analysis of 111In-labeled liposomal doxorubicin in murine glioblastoma after blood-brain barrier disruption by focused ultrasound. PLoS One. 2012;7(9):e45468. doi: 10.1371/journal.pone.0045468
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