Effect of the Metal Center on the Antitumor Activity of the Analogous Dinuclear Spermine Chelates (PdCl2)2(Spermine) and (PtCl2)2(Spermine)

Soares, Ana Sofia; Fiuza, Sónia M.; Gonçalves, M. Sameiro T.; Carvalho, Luis Batista de; Marques, M. P. M.; Urbano, Ana M.

doi:10.2174/157018007781788516

Cited by 34 publications

(26 citation statements)

References 18 publications

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“…The detailed knowledge of the molecular basis of the cDDP-guanine/adenine and cDDPglutathione interplay gathered in this work will pave the way for future studies on other platinum and palladium-based agents previously characterized by the authors and assessed as to their cytotoxicity towards several human cancer cell lines. [29][30][31][32][33][34][35][36][37] This will provide valuable clues for the rational design of novel cisplatin-like drugs, displaying a higher efficiency, lower toxicity, decreased acquired resistance and possible oral administration. …”

Section: Introductionmentioning

confidence: 99%

A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance

Marques

Gianolio

Cibin

et al. 2015

Phys. Chem. Chem. Phys.

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The interaction of the widely used anticancer drug cisplatin with DNA bases was studied by EXAFS and vibrational spectroscopy (FTIR, Raman and INS), coupled with DFT/plane-wave calculations. Detailed information was obtained on the local atomic structure around the Pt(II) centre, both in the cisplatinpurine (adenine and guanine) and cisplatin-glutathione adducts. Simultaneous neutron and Raman scattering experiments allowed us to obtain a reliable and definite picture of this cisplatin interplay with its main pharmacological target (DNA), at the molecular level. The vibrational experimental spectra were fully assigned in the light of the calculated pattern for the most favoured geometry of each drug-purine adduct, and cisplatin's preference for guanine (G) relative to adenine (A) within the DNA double helix was experimentally verified: a complete N by S substitution in the metal coordination sphere was only observed for [cDDP-A 2 ], reflecting a somewhat weaker Pt-A binding relative to Pt-G. The role of glutathione on the drug's pharmacokinetics, as well as on the stability of platinated DNA adducts, was evaluated as this is the basis for glutathione-mediated intracellular drug scavenging and in vivo resistance to Pt-based anticancer drugs. Spectroscopic evidence of the metal's preference for glutathione's sulfur over purine's nitrogen binding sites was gathered, at least two sulfur atoms being detected in platinum's first coordination sphere.

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Section: Introductionmentioning

confidence: 99%

A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance

Marques

Gianolio

Cibin

et al. 2015

Phys. Chem. Chem. Phys.

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“…1A). 14 This complex was shown to display interesting antiproliferative properties against cancer cells, 15,16 although it presents a quite different chemical composition and structure from the array of active Pd(II) compounds reported in the literature to date. An understanding of the SARs determining this type of compound's activity is fundamental for interpreting the biochemical mechanisms underlying their biological effect (e.g.…”

Section: Introductionmentioning

confidence: 99%

Conformational insights and vibrational study of a promising anticancer agent: the role of the ligand in Pd(ii)–amine complexes

et al. 2015

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A conformational and vibrational analysis of an antiproliferative spermine-based dinuclear Pd(II) complex (Pd 2 -Spm) is reported. Density functional theory coupled to all-electron basis sets was used to perform quantum mechanical calculations aimed at determining the strategy best suited for accurately representing this molecule and achieving an optimal accordance with the experimental data. The structural parameters and the vibrational frequencies predicted by the calculations are compared with the corresponding experimental data. The results support a relationship between the strength of the metal-ligand bonds and the antitumor activity of the compound.

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“…DENSPM was generously provided by Dr R. Merriman from Pfizer Pharmaceuticals (Ann Arbor, MI). The Ptspermine and Pd-spermine complexes have been synthesized as described before (26). [ 14 C]-acetyl-Coenzyme A (no.…”

Section: Methodsmentioning

confidence: 99%

“…In this regard, multinuclear Pt (II)-and Pd (II)-spermine complexes comprising cisplatinlike moieties linked by variable length alkanediammine chains were synthesized and constitute a promising class of anticancer agents, the most successful case being the trinuclear compound BBR3464 (25). These spermine complexes have been shown to possess antiproliferative properties towards human cancer cells lines (22,23,26), the Pd (II)-spermine complex having a damaging interaction with both DNA and the cytoskeleton (Fiuza et al, unpublished data).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Pt-, Pd-spermine complexes for their effect on polyamine pathway and cisplatin resistance in A2780 ovarian carcinoma cells

Tummala

Diegelman²,

Fiuza³

et al. 2010

Oncol Rep

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Abstract.We have previously showed that platinum drugs up-regulate SSAT and SMO and down-regulate ODC and SAMDC in the polyamine pathway. Several studies including our own established that platinum drugs combined with polyamine analog DENSPM produces synergistic increase in SSAT activity with polyamine depletion. Since polyamine pathway is an important therapeutic target, we investigated whether agents containing both platinum and polyamines have similar effects on the polyamine pathway. Two complexes i) Pt-spermine with two cisplatin molecules linked to a spermine in the center and ii) Pd-spermine with similar structure i, but Pd (II) substituted for Pt (II) were analyzed with respect to their effect on the expression of genes in polyamine pathway, SSAT and SMO protein expression, SSAT activity and polyamine pools. Pt-, Pd-spermine complexes induced significant down-regulation of SMO, arginase 2 and NRF-2, with no change in SSAT, while cisplatin as a single agent or in combination with DENSPM induced significant up-regulation of SSAT and SMO. The SSAT activity was not induced by either Pt-or Pd-spermine in A2780 cells; SMO protein levels were significantly elevated compared to the no-drug control and to a similar extent as cisplatin/DENSPM. The Pd-spm treatment induced a fall in putrescine levels to 33%, spermidine to 62% and spermine to 72% while Pt-spm did not induce such a decline. Comparative cytotoxicity studies in A2780 cells indicated the potency to be cisplatin> Pd-Spm>Pt-Spm. Although both complexes exhibit a lower potency, the degree of resistance itself is much lower for Pt-spermine and Pd-spermine in that order (2.5 and 7.5, respectively) compared to cisplatin (~12) as tested in cisplatin resistant A2780/CP cells. These studies suggest that Pd (II)-polyamine complexes may constitute a promising group of inorganic compounds for further studies in the development of novel chemotherapy/adjuvant chemotherapy strategies.

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Effect of the Metal Center on the Antitumor Activity of the Analogous Dinuclear Spermine Chelates (PdCl2)2(Spermine) and (PtCl2)2(Spermine)

Cited by 34 publications

References 18 publications

A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance

A molecular view of cisplatin's mode of action: interplay with DNA bases and acquired resistance

Conformational insights and vibrational study of a promising anticancer agent: the role of the ligand in Pd(ii)–amine complexes

Characterization of Pt-, Pd-spermine complexes for their effect on polyamine pathway and cisplatin resistance in A2780 ovarian carcinoma cells

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