{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T10:56:15Z","timestamp":1761648975528,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T00:00:00Z","timestamp":1642550400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["UIDB\/QUI\/50006\/2020","UIDB\/00070\/2020","PTDC\/QEQ-MED\/1890\/2014","PD\/BD\/135460\/2017"],"award-info":[{"award-number":["UIDB\/QUI\/50006\/2020","UIDB\/00070\/2020","PTDC\/QEQ-MED\/1890\/2014","PD\/BD\/135460\/2017"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomedicines"],"abstract":"<jats:p>Pd2Spm is a dinuclear palladium(II)-spermine chelate with promising anticancer properties against triple-negative breast cancer (TNBC), a breast carcinoma subset with poor prognosis and limited treatment options. The present study evaluated the in vitro and in vivo anticancer effects of Pd2Spm compared to the reference metal-based drug cisplatin. Triple-negative breast cancer MDA-MB-231 cells, non-cancerous MCF-12A breast cells and chorioallantoic membrane (CAM) assay were used for antiproliferative, antimigratory and antiangiogenic studies. For an in vivo efficacy study, female CBA nude mice with subcutaneously implanted MDA-MB-231 breast tumors were treated with Pd2Spm (5 mg\/kg\/day) or cisplatin (2 mg\/kg\/day) administered intraperitoneally during 5 consecutive days. Promising selective antiproliferative activity of Pd2Spm was observed in MDA-MB-231 cells (IC50 values of 7.3\u20138.3 \u00b5M), with at least 10-fold lower activity in MCF-12A cells (IC50 values of 89.5\u2013228.9 \u00b5M). Pd2Spm inhibited the migration of MDA-MB-231 cells, suppressed angiogenesis in CAM and decreased VEGF secretion from MDA-MB-231 cells with similar potency as cisplatin. Pd2Spm-treated mice showed a significant reduction in tumor growth progression, and tumors evidenced a reduction in the Ki-67 proliferation index and number of mitotic figures, as well as increased DNA damage, similar to cisplatin-treated animals. Encouragingly, systemic toxicity (hematotoxicity and weight loss) observed in cisplatin-treated animals was not observed in Pd2Spm-treated mice. The present study reports, for the first time, promising cancer selectivity, in vivo antitumor activity towards TNBC and a low systemic toxicity of Pd2Spm. Thus, this agent may be viewed as a promising Pd(II) drug candidate for the treatment of this type of low-prognosis neoplasia.<\/jats:p>","DOI":"10.3390\/biomedicines10020210","type":"journal-article","created":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T08:20:57Z","timestamp":1642580457000},"page":"210","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Pd2Spermine Complex Shows Cancer Selectivity and Efficacy to Inhibit Growth of Triple-Negative Breast Tumors in Mice"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9257-7020","authenticated-orcid":false,"given":"Martin","family":"Vojtek","sequence":"first","affiliation":[{"name":"LAQV\/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2583-5624","authenticated-orcid":false,"given":"Salom\u00e9","family":"Gon\u00e7alves-Monteiro","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"given":"Patr\u00edcia","family":"\u0160eminsk\u00e1","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"given":"Katar\u00edna","family":"Valov\u00e1","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"given":"Loreto","family":"Bell\u00f3n","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"given":"Patr\u00edcia","family":"Dias-Pereira","sequence":"additional","affiliation":[{"name":"ICBAS\u2014Instituto de Ci\u00eancias Biom\u00e9dicas de Abel Salazar, University of Porto, 4050-313 Porto, Portugal"}]},{"given":"Franklim","family":"Marques","sequence":"additional","affiliation":[{"name":"Clinical Analysis Unit, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8391-0055","authenticated-orcid":false,"given":"Maria P. M.","family":"Marques","sequence":"additional","affiliation":[{"name":"\u201cMolecular Physical-Chemistry\u201d R&D Unit, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"},{"name":"Department of Life Sciences, University of Coimbra, 3000-456 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1280-3321","authenticated-orcid":false,"given":"Ana L. M.","family":"Batista de Carvalho","sequence":"additional","affiliation":[{"name":"\u201cMolecular Physical-Chemistry\u201d R&D Unit, Department of Chemistry, University of Coimbra, 3004-535 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3045-2553","authenticated-orcid":false,"given":"Helder","family":"Mota-Filipe","sequence":"additional","affiliation":[{"name":"iMed.ULisboa, Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, Portugal"}]},{"given":"Isabel M. P. L. V. O.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laboratory of Bromatology and Hydrology, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4668-9360","authenticated-orcid":false,"given":"Carmen","family":"Diniz","sequence":"additional","affiliation":[{"name":"LAQV\/REQUIMTE, Laboratory of Pharmacology, Department of Drug Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Wu, Q., Siddharth, S., and Sharma, D. (2021). Triple Negative Breast Cancer: A Mountain Yet to Be Scaled Despite the Triumphs. Cancers, 13.","DOI":"10.3390\/cancers13153697"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Bianchini, G., De Angelis, C., Licata, L., and Gianni, L. (2021). Treatment Landscape of Triple-Negative Breast Cancer\u2014Expanded Options, Evolving Needs. Nat. Rev. Clin. Oncol., 274.","DOI":"10.1038\/s41571-021-00565-2"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"512","DOI":"10.3892\/ol.2021.12773","article-title":"Triple-negative Breast Cancer: A Run-through of Features, Classification and Current Therapies (Review)","volume":"22","author":"Manjunath","year":"2021","journal-title":"Oncol. Lett."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1159\/000515353","article-title":"The Impact of Platinum-Containing Chemotherapies in Advanced Triple-Negative Breast Cancer: Meta-Analytical Approach to Evaluating Its Efficacy and Safety","volume":"44","author":"Yang","year":"2021","journal-title":"Oncol. Res. Treat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1634\/theoncologist.2016-0319","article-title":"A Systematic Review of Strategies to Prevent Cisplatin-Induced Nephrotoxicity","volume":"22","author":"Crona","year":"2017","journal-title":"Oncologist"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1016\/j.drudis.2019.02.012","article-title":"Anticancer Activity of Palladium-Based Complexes against Triple-Negative Breast Cancer","volume":"24","author":"Vojtek","year":"2019","journal-title":"Drug Discov. Today"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5993","DOI":"10.1002\/slct.202001361","article-title":"Cytotoxicity of Platinum and Palladium Chelates against Osteosarcoma","volume":"5","author":"Martins","year":"2020","journal-title":"ChemistrySelect"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1111\/j.1747-0285.2011.01081.x","article-title":"Biologic Activity of a Dinuclear Pd(II)-Spermine Complex Toward Human Breast Cancer","volume":"77","author":"Fiuza","year":"2011","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_10","first-page":"15","article-title":"Characterization of Pt-, Pd-Spermine Complexes for Their Effect on Polyamine Pathway and Cisplatin Resistance in A2780 Ovarian Carcinoma Cells","volume":"24","author":"Tummala","year":"2010","journal-title":"Oncol. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Batista de Carvalho, A.L.M., Medeiros, P.S.C., Costa, F.M., Ribeiro, V.P., Sousa, J.B., Diniz, C., and Marques, M.P.M. (2016). Anti-Invasive and Anti-Proliferative Synergism between Docetaxel and a Polynuclear Pd-Spermine Agent. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0167218"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8773","DOI":"10.1039\/C5CS00201J","article-title":"Multi-Platinum Anti-Cancer Agents. Substitution-Inert Compounds for Tumor Selectivity and New Targets","volume":"44","author":"Farrell","year":"2015","journal-title":"Chem. Soc. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3201","DOI":"10.1039\/C5DT03919C","article-title":"Metal-Based Drugs That Break the Rules","volume":"45","author":"Allardyce","year":"2016","journal-title":"Dalt. Trans."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2013\/287353","article-title":"Platinum and Palladium Polyamine Complexes as Anticancer Agents: The Structural Factor","volume":"2013","author":"Marques","year":"2013","journal-title":"ISRN Spectrosc."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Vojtek, M., Gon\u00e7alves-Monteiro, S., Pinto, E., Kalivodov\u00e1, S., Almeida, A., Marques, M.P.M., de Carvalho, A.L.M.B., Martins, C.B., Mota-Filipe, H., and Ferreira, I.M.P.L.V.O. (2021). Preclinical Pharmacokinetics and Biodistribution of Anticancer Dinuclear Palladium(II)-Spermine Complex (Pd2Spm) in Mice. Pharmaceuticals, 14.","DOI":"10.3390\/ph14020173"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2702","DOI":"10.1039\/C6CP05198G","article-title":"Intracellular Water-an Overlooked Drug Target? Cisplatin Impact in Cancer Cells Probed by Neutrons","volume":"19","author":"Marques","year":"2017","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Marques, M.P.M., Batista de Carvalho, A.L.M., Mamede, A.P., Dopplapudi, A., Rudi\u0107, S., Tyagi, M., Garcia Sakai, V., and Batista de Carvalho, L.A.E. (2020). A New Look into the Mode of Action of Metal-Based Anticancer Drugs. Molecules, 25.","DOI":"10.3390\/molecules25020246"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1080\/0144235X.2020.1700083","article-title":"Intracellular Water as a Mediator of Anticancer Drug Action","volume":"39","author":"Marques","year":"2020","journal-title":"Int. Rev. Phys. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Carneiro, T.J., Ara\u00fajo, R., Vojtek, M., Gon\u00e7alves-Monteiro, S., Diniz, C., de Carvalho, A.L.M.B., Marques, M.P.M., and Gil, A.M. (2021). Novel Insights into Mice Multi-Organ Metabolism upon Exposure to a Potential Anticancer Pd(II)-Agent. Metabolites, 11.","DOI":"10.3390\/metabo11020114"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1002\/(SICI)1522-2675(19990707)82:7<1025::AID-HLCA1025>3.0.CO;2-1","article-title":"Palladium(II) and Platinum(II) Polyamine Complexes: X-Ray Crystal Structures of (SP-4-2)-Chloro{N-[(3-Amino-\u039aN) Propyl]Propane-1,3-Diamine- \u039aN,\u039aN\u2019}palladium(1+) Tetrachloropalladate (2-) (2:1) and (R,S)- Tetrachloro[\u03bc-(Spermine)]Dipalladium(II) (={\u03bc-{N,N\u2019","volume":"82","author":"Codina","year":"1999","journal-title":"Helv. Chim. Acta"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6274","DOI":"10.1039\/C5NJ01088H","article-title":"Conformational Insights and Vibrational Study of a Promising Anticancer Agent: The Role of the Ligand in Pd(II)-Amine Complexes","volume":"39","author":"Fiuza","year":"2015","journal-title":"New J. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1002\/cphc.201001067","article-title":"Inelastic Neutron Scattering Study of Pt II Complexes Displaying Anticancer Properties","volume":"12","author":"Marques","year":"2011","journal-title":"ChemPhysChem"},{"key":"ref_23","first-page":"421","article-title":"N:NIH(S)II-Nu\/Nu Mice With Combined Immunodeficiency: A New Model for Human Tumor Heterotransplantation","volume":"65","author":"Azar","year":"1980","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1007\/BF00391826","article-title":"Estimation of Liver Tumor Volume Using Different Formulas-An Experimental Study in Rats","volume":"105","author":"Carlsson","year":"1983","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1111\/j.1365-2559.1991.tb00229.x","article-title":"Pathological Prognostic Factors in Breast Cancer. I. The Value of Histological Grade in Breast Cancer: Experience from a Large Study with Long-Term Follow-Up","volume":"19","author":"Elston","year":"1991","journal-title":"Histopathology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-15885-6","article-title":"Andy\u2019s Algorithms: New Automated Digital Image Analysis Pipelines for FIJI","volume":"7","author":"Law","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"73","DOI":"10.2174\/1389201003379040","article-title":"The Chick Embryo Chorioallantoic Membrane as a Model for in Vivo Research on Anti-Angiogenesis","volume":"1","author":"Ribatti","year":"2000","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_28","unstructured":"Carpentier, G., Martinelli, M., Courty, J., and Cascone, I. (2012). Angiogenesis Analyzer for ImageJ. 4th ImageJ User and Developer Conference Proceedings, Mondorf-les-Bains."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Percie du Sert, N., Hurst, V., Ahluwalia, A., Alam, S., Avey, M.T., Baker, M., Browne, W.J., Clark, A., Cuthill, I.C., and Dirnagl, U. (2020). The ARRIVE Guidelines 2.0: Updated Guidelines for Reporting Animal Research. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000410"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/s00412-018-0659-8","article-title":"Ki-67: More than a Proliferation Marker","volume":"127","author":"Sun","year":"2018","journal-title":"Chromosoma"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.tranon.2016.07.002","article-title":"Angiogenesis and Antiangiogenesis in Triple-Negative Breast Cancer","volume":"9","author":"Ribatti","year":"2016","journal-title":"Transl. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1039\/C8DT03266A","article-title":"Experimental and Theoretical Investigations of Cyclometalated Ruthenium(II) Complex Containing CCC-Pincer and Anti-Inflammatory Drugs as Ligands: Synthesis, Characterization, Inhibition of Cyclooxygenase and in Vitro Cytotoxicity Activities in Various Can","volume":"48","author":"Tabrizi","year":"2019","journal-title":"Dalt. Trans."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/0162-0134(93)85621-E","article-title":"Palladium(II) Compounds of Putrescine and Spermine. Synthesis, Characterization, and DNA-Binding and Antitumor Properties","volume":"52","author":"Zamora","year":"1993","journal-title":"J. Inorg. Biochem."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Per\u0161e, M. (2021). Cisplatin Mouse Models: Treatment, Toxicity and Translatability. Biomedicines, 9.","DOI":"10.3390\/biomedicines9101406"},{"key":"ref_35","first-page":"246","article-title":"Macrocytic Anemia during Low-Dose Cisplatin and 5-Fluorouracil through Implanted Infusion Port for Unresectable Hepatobilliary Malignancies","volume":"25","author":"Yamamoto","year":"2005","journal-title":"Anticancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/j.bbrc.2020.07.059","article-title":"Pivalopril Improves Anti-Cancer Efficiency of CDDP in Breast Cancer through Inhibiting Proliferation, Angiogenesis and Metastasis","volume":"533","author":"Fei","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.bcp.2007.04.003","article-title":"Cisplatin and Doxorubicin Repress Vascular Endothelial Growth Factor Expression and Differentially Down-Regulate Hypoxia-Inducible Factor I Activity in Human Ovarian Cancer Cells","volume":"74","author":"Duyndam","year":"2007","journal-title":"Biochem. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"104229","DOI":"10.1016\/j.mvr.2021.104229","article-title":"Palladium (II) Complex and Thalidomide Intercept Angiogenic Signaling via Targeting FAK\/Src and Erk\/Akt\/PLC\u03b3 Dependent Autophagy Pathways in Human Umbilical Vein Endothelial Cells","volume":"138","author":"Aydinlik","year":"2021","journal-title":"Microvasc. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4957","DOI":"10.1016\/j.ejmech.2011.07.055","article-title":"Anti-Cancer Activity of a Novel Palladium(II) Complex on Human Breast Cancer Cells in Vitro and in Vivo","volume":"46","author":"Ulukaya","year":"2011","journal-title":"Eur. J. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4948","DOI":"10.1016\/j.bmc.2014.06.039","article-title":"Apoptosis-Inducing Effect of a Palladium(II) Saccharinate Complex of Terpyridine on Human Breast Cancer Cells in Vitro and in Vivo","volume":"22","author":"Ari","year":"2014","journal-title":"Bioorg. Med. Chem."}],"container-title":["Biomedicines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2227-9059\/10\/2\/210\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:04:03Z","timestamp":1760133843000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2227-9059\/10\/2\/210"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,19]]},"references-count":40,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["biomedicines10020210"],"URL":"https:\/\/doi.org\/10.3390\/biomedicines10020210","relation":{},"ISSN":["2227-9059"],"issn-type":[{"type":"electronic","value":"2227-9059"}],"subject":[],"published":{"date-parts":[[2022,1,19]]}}}