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.

A New Look into the Mode of Action of Metal-Based Anticancer Drugs

“…Cytotoxicity arises from the selective covalent binding of the metal ions to DNA purine bases at more than one site within the double helix, yielding long-range interstrand adducts. These agents have been synthesised and extensively investigated by the team, to provide a comprehensive set of data on (i) cytotoxicity towards several human cancer cells [6][7][8][9][10], (ii) interactions with DNA and glutathione-mediated resistance pathways [11,12] and (iii) impact on cellular metabolism and intracellular water [12][13][14][15][16]. Vibrational spectroscopy techniques were applied (including inelastic neutron scattering and synchrotron radiation-Fourier transform infrared (FTIR)) coupled to theoretical simulations [4,17,18], as well as synchrotron-based Extended X-ray Absorption Fine Structure (EXAFS) [11].…”

“…Vibrational spectroscopy techniques were applied (including inelastic neutron scattering and synchrotron radiation-Fourier transform infrared (FTIR)) coupled to theoretical simulations [4,17,18], as well as synchrotron-based Extended X-ray Absorption Fine Structure (EXAFS) [11]. The dinuclear complex Pd 2 Spm (Spm = spermine, H 2 N(CH 2 ) 3 NH(CH 2 ) 4 NH(CH 2 ) 3 NH 2 ), in particular, has yielded quite promising results towards human triple negative (metastatic) breast cancer, coupled to lower toxicity in non-tumorigenic cells [8,10].…”

Anticancer Drug Impact on DNA – A Study by Neutron Spectrocopy, Synchrotron-based FTIR and EXAFS

“…The dinuclear complexes Pt 2 Spm and Pd 2 Spm have been studied by the authors in the last few years and have been shown to act as promising anticancer agents towards human metastatic breast cancer (Batista de Carvalho et al, 2016a, Batista de Carvalho et al, 2016b, Fiuza et al, 2011, Marques et al, 2002, Silva et al, 2013 and osteosarcoma (Lamego et al, 2017). A multidisciplinary study was presently carried out to attain complementary structural and dynamical information on their interplay with DNA (their main pharmacological target), using QENS measurements, SR-FTIR and SR-EXAFS/XANES.…”

“…(Kelland, 2007, Marques, 2013, Wheate, Walker et al, 2010 Among these, polynuclear multifunctional Pt(II) and Pd(II) chelates with flexible biogenic polyamines as bridging ligands have been synthetized by the authors and evaluated as to their effect on several types of human neoplasias, namely the low prognosis, highly metastatic triple negative breast cancer against which a Pd(II) agent (Pd 2 Spm, Spm=spermine, H 2 N(CH 2 ) 3 NH(CH 2 ) 4 NH(CH 2 ) 3 NH 2 ) has yielded particularly promising results. (Fiuza, Holy et al, 2011) A number of studies have been conducted in the last few years on these Pt-and Pd-based complexes, reporting conformational profiles (Batista de Carvalho, Parker et al, 2018, Fiuza, Amado et al, 2015, Marques, Valero et al, 2013 and pharmacokinetic/pharmacodynamic behaviour, (Corduneanu, Chiorcea-Paquim et al, 2010, Marques, Gianolio et al, 2015 and the effect on different human cancers(Batista de Carvalho, Medeiros et al, 2016a, Fiuza, Amado et al, 2006, Fiuza et al, 2011, Marques, Girao et al, 2002, Silva, Andersson et al, 2013, Silva, Fiuza et al, 2014, Soares, Fiuza et al, 2007, Tassoni, Bagni et al, 2010, Teixeira, Seabra et al, 2004, Tummala, Diegelman et al, 2010 including their impact on cellular biochemical profile. (Batista de Carvalho, Pilling et al, 2016b, Lamego, Marques et al, 2017, Marques, Batista de Carvalho et al, 2017 Unconventional pathways of cytotoxicity were disclosed, which are recognized to lead to an improved therapeutic efficiency coupled to a lower toxicity.…”

Metabolic Aspects of Palladium(II) Potential Anti-Cancer Drugs

“…However, such compounds are typically associated to serious systemic toxicity and acquired resistance (mainly via interaction with glutathione and metallothioneins) ( 3 ). Therefore, other metal complexes have been tested, namely containing ruthenium ( 4 , 5 ), titanium ( 6 ), gold ( 7 ), and palladium, Pd ( 8 – 11 ). Pd(II) compounds have attracted much attention due to the similarity of the metal center to Pt(II) (electronic structure and coordination chemistry) ( 12 , 13 ).…”