Platinum(ii/iv) complexes containing ethylenediamine-N,N′-di-2/3-propionate ester ligands induced caspase-dependent apoptosis in cisplatin-resistant colon cancer cells

Kaluđerović, Goran N.; Mijatović, Sanja; Zmejkovski, Bojana B.; Bulatović, Mirna; Gómez‐Ruiz, Santiago; Mojić, Marija; Steinborn, Dirk; Miljković, Djordje; Schmidt, Harry; Stošić‐Grujičić, Stanislava; Sabo, Tibor J.; Maksimović‐Ivanić, Danijela

doi:10.1039/c2mt20058a

Cited by 37 publications

(14 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…So far, ROS was only reported in the case of tetrachlorido platinum(IV) complexes. 37 For determination of ROS levels produced during platinum treatment, cells were stained with DCFH-DA (2 0 ,7 0 -dichlorofluorescein diacetate) and afterwards treated with platinum complexes for 30 min (Fig. 11).…”

Section: Involvement Of Oxidative Stress In Pt IV Cytotoxicitymentioning

confidence: 99%

Influence of reducing agents on the cytotoxic activity of platinum(iv) complexes: induction of G2/M arrest, apoptosis and oxidative stress in A2780 and cisplatin resistant A2780cis cell lines

et al. 2015

View full text Add to dashboard Cite

The concept of Pt(IV) prodrug design is one advanced strategy to increase the selectivity for cancer cells and to reduce systemic toxicity in comparison to established platinum-based chemotherapy. Pt(IV) complexes are thought to be activated by reduction via physiological reductants, such as ascorbic acid or glutathione. Nevertheless, only few investigations on the link between the reduction rate, which is influenced by the reductant, and the ligand sphere of the Pt(IV) metal centre have been performed so far. Herein, we investigated a set of Pt(IV) compounds with varying rates of reduction with respect to their cytotoxicity and drug accumulation in A2780 and A2780cis ovarian cancer cell lines, their influence on the cell cycle, efficiency of triggering apoptosis, and ability to interfere with plasmid DNA (pUC19). The effects caused by Pt(IV) compounds were compared without or with extracellularly added ascorbic acid and glutathione (or its precursor N-acetylcysteine) to gain understanding of the impact of increased levels of the reductant on the activity of such complexes. Our results demonstrate that reduction is required prior to plasmid interaction. Furthermore, the rate of reduction is crucial for the efficiency of this set of Pt(IV) compounds. The substances that are reduced least likely showed similar performances, whereas the fastest reducing substance was negatively affected by an increased extracellular level of reducing agents, with reduced cytotoxicity and lower efficiency in inducing apoptosis and G2/M arrest. These results confirm the connection between reduction and activity, and prove the strong impact of the reduction site on the activity of Pt(IV) complexes.

show abstract

Section: Involvement Of Oxidative Stress In Pt IV Cytotoxicitymentioning

confidence: 99%

Influence of reducing agents on the cytotoxic activity of platinum(iv) complexes: induction of G2/M arrest, apoptosis and oxidative stress in A2780 and cisplatin resistant A2780cis cell lines

et al. 2015

View full text Add to dashboard Cite

show abstract

“…16−26 These ligands, obtained by structural variations of the aminocarboxylato arms and alkyl groups of the ester moiety (normal, branched chains, rings), yielded a large library of such molecules (Fig. 1, D) were tested against various cancer lines and normal cells and moderate or low activity was found, 20,21,23,24,29,30 except for (S,S)-Et 2 eddch that had the lowest IC 50 values ca. In most cases, high cytotoxic action was accomplished when coordinating to platinum ions, but some of the esters, in fact, showed serious activity themselves.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and high in vitro cytotoxicity of some (S,S)-ethylenediamine-N,N’-di-2-propanoate dihydrochloride esters

Pantelić

Zmejkovski

Stanojković

et al. 2014

JSCS

View full text Add to dashboard Cite

A novel (S,S)-R 2 eddip ester, O,O′-diisopentyl-(S,S)-ethylenediamine--N,N′-di-2-propanoate dihydrochloride (1) was synthesized and characterized by IR, 1 H-and 13 C-NMR spectroscopy, mass spectroscopy and elemental analysis. In vitro antitumor action of 1, and two more R 2 eddip esters, dialkyl (S,S)-ethylenediamine-N,N′-di-2-propanoate dihydrochlorides, obtained before (alkyl = n-Bu or n-Pe, 2 and 3, respectively), was determined against cervix adenocarcinoma (HeLa), human melanoma (Fem-x), human chronic myelogenous leukemia (K562) cells, and a non-cancerous cell line human embryonic lung fibroblast (MRC-5), using the microculture tetrazolium test MTT assay. Esters 1-3 showed higher cytotoxicity and better selectivity in comparison to cisplatin, used as reference compound. The highest activity was expressed by 1, with IC 50 (Fem-x) value of 1.51±0.09 µM.

show abstract

“…The possibility of Pt(IV) complexes inducing the formation of reactive oxygen species (ROS) has been considered only recently 41 42 . Because of metabolic and signaling aberrations, cancer cells already have elevated ROS levels and the induction of further oxidative stress has been recognized as an attractive strategy to selectively kill cancer cells 43 . On these bases, herein we investigated the potential antitumor activity of new Pt(IV) complexes bearing IAA and IPA as axial ligands, focusing our attention on ROS production and mitochondrial membrane potential perturbation.…”

mentioning

confidence: 99%

Oxidative Stress Induced by Pt(IV) Pro-drugs Based on the Cisplatin Scaffold and Indole Carboxylic Acids in Axial Position

Tolan

Gandin

Morrison

et al. 2016

Sci Rep

View full text Add to dashboard Cite

The use of Pt(IV) complexes as pro-drugs that are activated by intracellular reduction is a widely investigated approach to overcome the limitations of Pt(II) anticancer agents. A series of ten mono- and bis-carboxylated Pt(IV) complexes with axial indole-3-acetic acid (IAA) and indole-3-propionic acid (IPA) ligands were synthesized and characterized by elemental analysis, ESI-MS, FT-IR, 1H and 195Pt NMR spectroscopy. Cellular uptake, DNA platination and cytotoxicity against a panel of human tumor cell lines were evaluated. All the complexes are able to overcome cisplatin-resistance and the most potent complex, cis,cis,trans-[Pt(NH3)2Cl2(IPA)(OH)] was on average three times more active than cisplatin. Mechanistic studies revealed that the trend in cytotoxicity of the Pt(IV) complexes is primarily consistent with their ability to accumulate into cancer cells and to increase intracellular basal reactive oxygen species levels, which in turn results in the loss of mitochondrial membrane potential and apoptosis induction. The role of the indole acid ligand as a redox modulator is discussed.

show abstract

Platinum(ii/iv) complexes containing ethylenediamine-N,N′-di-2/3-propionate ester ligands induced caspase-dependent apoptosis in cisplatin-resistant colon cancer cells

Cited by 37 publications

References 40 publications

Influence of reducing agents on the cytotoxic activity of platinum(iv) complexes: induction of G2/M arrest, apoptosis and oxidative stress in A2780 and cisplatin resistant A2780cis cell lines

Influence of reducing agents on the cytotoxic activity of platinum(iv) complexes: induction of G2/M arrest, apoptosis and oxidative stress in A2780 and cisplatin resistant A2780cis cell lines

Synthesis and high in vitro cytotoxicity of some (S,S)-ethylenediamine-N,N’-di-2-propanoate dihydrochloride esters

Oxidative Stress Induced by Pt(IV) Pro-drugs Based on the Cisplatin Scaffold and Indole Carboxylic Acids in Axial Position

Contact Info

Product

Resources

About