title: Anti-Invasive and Anti-Proliferative Synergism between Docetaxel and a Polynuclear Pd-Spermine Agent.
abstract: The present work is aimed at evaluating the antitumour properties of a Pd(II) dinuclear complex with the biogenic polyamine spermine, by investigating: i) the anti-angiogenic and anti-migration properties of a Pd(II) dinuclear complex with spermine (Pd2Spm); ii) the anti-proliferative activity of Pd2Spm against a triple negative human breast carcinoma (MDA-MB-231); and finally iii) the putative interaction mediated by combination of Pd2Spm with Docetaxel. Anti-invasive (anti-angiogenic and anti-migratory) as well as anti-proliferative capacities were assessed, for different combination schemes and drug exposure times, using the CAM assay and VEGFR2 activity measurement, the MatrigelTM method and the SRB proliferation test. The results thus obtained evidence the ability of Pd2Spm to restrict angiogenesis and cell migration: Pd2Spm induced a marked inhibition of migration (43.8±12.2%), and a higher inhibition of angiogenesis (81.8±4.4% for total length values, at 4 μM) as compared to DTX at the clinical dosage 4x10-2 μM (26.4±14.4%; n = 4 to 11). Combination of Pd2Spm/DTX was more effective as anti-invasive and anti-proliferative than DTX or Pd2Spm in sole administration, which is compatible with the occurrence of synergism: for the anti-angiogenic effect, IC50(Pd2Spm/DTX) = 0.5/0.5x10-2 μM vs IC50(DTX) = 1.7x10-2 μM and IC50(Pd2Spm) = 1.6 μM. In conclusion, the reported effects of Pd2Spm on angiogenesis, migration and proliferation showed that this compound is a promising therapeutic agent against this type of breast cancer. Moreover, combined administration of Pd2Spm and DTX was found to trigger a substantial synergetic effect regarding angiogenesis inhibition as well as anti-migratory and anti-proliferative activities reinforcing the putative use of Pd(II) complexes in chemotherapeutic regimens. This is a significant outcome, aiming at the application of these combined strategies towards metastatic breast cancer (or other type of resistant cancers), justifying further studies that include pre-clinical trials.
authors.affiliation: Unidade de I&D Química-Física Molecular, Department of Chemistry, University of Coimbra, Coimbra, Portugal.
authors.forename: Ana L M
authors.initials: AL
authors.lastname: Batista de Carvalho
authors.affiliation: Unidade de I&D Química-Física Molecular, Department of Chemistry, University of Coimbra, Coimbra, Portugal.
authors.forename: Paula S C
authors.initials: PS
authors.lastname: Medeiros
authors.affiliation: Laboratory of Pharmacology, Department of Drug Science, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Costa
authors.affiliation: Laboratory of Pharmacology, Department of Drug Science, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors.forename: Vanessa P
authors.initials: VP
authors.lastname: Ribeiro
authors.affiliation: Laboratory of Pharmacology, Department of Drug Science, Faculty of Pharmacy, University of Porto, Porto, Portugal.|LAQV/REQUIMTE, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors.forename: Joana B
authors.initials: JB
authors.lastname: Sousa
authors.affiliation: Laboratory of Pharmacology, Department of Drug Science, Faculty of Pharmacy, University of Porto, Porto, Portugal.|LAQV/REQUIMTE, Faculty of Pharmacy, University of Porto, Porto, Portugal.
authors.forename: Carmen
authors.identifier: http://orcid.org/0000-0003-4668-9360
authors.initials: C
authors.lastname: Diniz
authors.affiliation: Unidade de I&D Química-Física Molecular, Department of Chemistry, University of Coimbra, Coimbra, Portugal.|Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, Coimbra, Portugal.
authors.forename: Maria P M
authors.initials: MP
authors.lastname: Marques
mesh_terms: D000818:Animals; D030161:Avian Proteins / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002642:Chick Embryo; D002645:Chickens; D000077143:Docetaxel; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010165:Palladium / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology*; D013096:Spermine / Q000819:agonists / Q000737:chemistry / Q000494:pharmacology*; D043823:Taxoids / Q000819:agonists / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D030161:Avian Proteins; D043823:Taxoids; D000077143:Docetaxel; D013096:Spermine; D010165:Palladium; D040301:Vascular Endothelial Growth Factor Receptor-2