Batista de Carvalho Ana L M, Medeiros Paula S C, Costa Francisco M, Ribeiro Vanessa P, Sousa Joana B, Diniz Carmen, Marques Maria P M
Unidade de I&D Química-Física Molecular, Department of Chemistry, University of Coimbra, Coimbra, Portugal.
Laboratory of Pharmacology, Department of Drug Science, Faculty of Pharmacy, University of Porto, Porto, Portugal.
PLoS One. 2016 Nov 23;11(11):e0167218. doi: 10.1371/journal.pone.0167218. eCollection 2016.
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.
本研究旨在通过研究以下方面来评估一种含有生物源多胺精胺的钯(II)双核配合物的抗肿瘤特性:i)钯(II)双核精胺配合物(Pd2Spm)的抗血管生成和抗迁移特性;ii)Pd2Spm对三阴性人乳腺癌(MDA-MB-231)的抗增殖活性;最后iii)Pd2Spm与多西他赛联合介导的假定相互作用。针对不同的联合方案和药物暴露时间,使用鸡胚绒毛尿囊膜(CAM)试验和VEGFR2活性测量、基质胶(MatrigelTM)方法以及磺酰罗丹明B(SRB)增殖试验评估了抗侵袭(抗血管生成和抗迁移)以及抗增殖能力。由此获得的结果证明了Pd2Spm限制血管生成和细胞迁移的能力:与临床剂量4×10-2 μM的多西他赛(DTX)(26.4±14.4%;n = 4至11)相比,Pd2Spm诱导了显著的迁移抑制(43.8±12.2%),以及更高的血管生成抑制(在4 μM时,总长度值的抑制率为81.8±4.4%)。Pd2Spm/DTX联合用药在抗侵袭和抗增殖方面比单独使用DTX或Pd2Spm更有效,这与协同作用的发生相一致:对于抗血管生成作用,IC50(Pd2Spm/DTX) = 0.5/0.5×10-2 μM,而IC50(DTX) = 1.7×10-2 μM,IC50(Pd2Spm) = 1.6 μM。总之,Pd2Spm对血管生成、迁移和增殖的上述作用表明,该化合物是针对此类乳腺癌的一种有前景的治疗剂。此外,发现Pd2Spm和DTX联合给药在抑制血管生成以及抗迁移和抗增殖活性方面引发了显著的协同作用,加强了钯(II)配合物在化疗方案中的假定应用。这是一个重要的结果,旨在将这些联合策略应用于转移性乳腺癌(或其他类型的耐药癌症),为包括临床前试验在内的进一步研究提供了依据。