RESUMEN
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.
Asunto(s)
Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Paladio/farmacología , Espermina/farmacología , Taxoides/farmacología , Animales , Proteínas Aviares/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Embrión de Pollo , Pollos , Docetaxel , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Femenino , Humanos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Paladio/agonistas , Paladio/química , Espermina/agonistas , Espermina/química , Taxoides/agonistas , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Inward rectifier K(+) channels (Kir2.1) exhibit an extraordinary rectifying feature in the current-voltage relationship. We have previously showed that the bundle-crossing region of the transmembrane domain constitutes the crucial segment responsible for the polyamine block. In this study, we demonstrated that the major blocking effect of intracellular Mg(2+) on Kir2.1 channels is also closely correlated with K(+) current flow, and the coupled movements of Mg(2+) and K(+) seem to happen in the same flux-coupling segment of the pore as polyamines. With a preponderant outward K(+) flow, intracellular Mg(2+) would also be pushed to and thus stay at the outermost site of a flux-coupling segment in the bundle-crossing region of Kir2.1 channels to block the pore, although with a much lower apparent affinity than spermine (SPM). However, in contrast to the evident possibilities of outward exit of SPM through the channel pore especially during strong membrane depolarization, intracellular Mg(2+) does not seem to traverse the Kir2.1 channel pore in any case. Intracellular Mg(2+) and SPM therefore may have a synergistic action on the pore-blocking effect, presumably via prohibition of the outward exit of the higher-affinity blocking SPM by the lower-affinity Mg(2+).
Asunto(s)
Magnesio/metabolismo , Bloqueadores de los Canales de Potasio/metabolismo , Canales de Potasio de Rectificación Interna/antagonistas & inhibidores , Canales de Potasio de Rectificación Interna/metabolismo , Espermina/metabolismo , Animales , Transporte Iónico/fisiología , Magnesio/agonistas , Ratones , Espermina/agonistas , Xenopus laevisRESUMEN
Intramuscular (i. m.) administration in the minimum effective dose (MED) of central analgesics of fentanyl and dipyrone, polyamine agonist spermine and also IEM-1460 (IEM-1460 is AMPA receptors antagonist and agonist of the NMDA polyamine receptor site) causes the maximal analgesic effect in the tail flick test in rats. The combined i.m. administration of dipyrone with IEM-1460 and spermine in threshold, noneffective alone doses according 1/5 part from their MED leads to decrease of MED dipyrone in the combination with IEM-1460 in 120 times, and MED dipyrone in combination with spermine--in 10 times. The combined i.m. administration of fentanyl with IEM-1460 and spermine in above mentioned threshold doses leads to decrease of MED fentanyl in the combination with IEM-1460 in 150 times, and MED fentanyl in the combination with spermine--in 15 times.