DNA binding mode of ruthenium complexes and relationship to tumor cell toxicity

Brabec, Viktor; Nováková, Olga

doi:10.1016/j.drup.2006.05.002

Cited by 358 publications

(248 citation statements)

References 69 publications

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“…The selective tumor targeting can be realized by the enhanced permeability and retention effect of the tumor tissue, and by the overexpression of transferrin receptors on cancer cells [16]. A further reason for their selectivity is the insufficient formation of new blood vessels in rapidly growing tumors that results in a more reductive environment as compared to normal tissue and facilitates Ru(III) reduction to Ru(II) ("activation by reduction" hypothesis) [17][18][19] and therefore ligand exchange and coordination towards biological targets such as DNA or proteins [7,12,20]. Therefore, reactions of anticancer metallodrugs with proteins are of considerable interest as these interactions might feature processes that are crucial for the biodistribution, the toxicity and even the mechanism of action of this important group of anticancer agents.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

et al. 2012

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Indazolium trans-[tetrachloridobis(1H-indazole)ruthenate(III)] (KP1019) and its Na + analogue (KP1339) are two of the most prominent non-platinum antitumor metal complexes currently undergoing clinical trials. After intravenous administration, they are known to bind to human serum albumin (HSA) in a non-covalent manner. In order to elucidate their HSA binding sites, displacement reactions with the established site markers warfarin and dansylglycine as well as bilirubin were monitored by spectrofluorimetry, ultrafiltration−UV-vis spectrophotometry and/or capillary zone electrophoresis. Conditional stability constants for the binding of KP1019 and KP1339 to sites I and II of HSA were determined, indicating that both Ru(III) compounds bind into both sites with moderately to strong affinity (logK 1 ' = 5.3-5.8). No preference for either binding site was found and similar results were obtained for both metal complexes, demonstrating low influence of the counter ion on the binding event.

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Section: Introductionmentioning

confidence: 99%

Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

et al. 2012

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“…On the other hand, (ImH)[trans-RuCl 4 (DMSO-S)(Im)] (known as Ru-NAMI-A) has successfully completed Phase I clinical trials as anticancer agent [16] and, interestingly, it has been recently inferred that its hydrolysis is a crucial step for the mechanism of its anticancer activity [17]. Finally, ruthenium complexes have been extensively studied also because of their ability of mimicking the binding of iron to molecules of biological significance, to exploit in such a way the mechanisms that the body has evolved for the transport of iron [18].…”

Section: Introductionmentioning

confidence: 99%

The interaction of native calf thymus DNA with FeIII-dipyrido[3,2-a:2′,3′-c]phenazine

Terenzi

Barone

Silvestri

et al. 2009

Journal of Inorganic Biochemistry

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a b s t r a c tThe mono and bis dipyrido[3,2-a:2 0 ,3 0 -c]phenazine (dppz) adducts of iron(III) chloride, i.e. [Fe(dppz)]Cl 3 and [Fe(dppz) 2 ]Cl 3 , have been synthesized and characterized. The interaction of the Fe III dppz hydrolyzed aquo complex with native calf thymus DNA has been monitored as a function of the metal complex-DNA molar ratio, by variable temperature UV absorption spectrophotometry, circular dichroism (CD) and fluorescence spectroscopy. The results obtained in solution at various ionic strength values give support for a tight intercalative binding of the Fe III dppz cation with DNA. In particular, the appearance of induced CD bands, caused by the addition of Fe III dppz, indicate the existence of a rigid metal complex-DNA-binding leading to dominating chiral organization of Fe III dppz species within the DNA double helix. The trend of selected CD bands with the molar concentration of Fe III dppz emphasizes that the presence of high amounts of metal complex induces also the formation of DNA-Fe III dppz supramolecular aggregates in solution. The analysis of fluorescence measurements allowed us to calculate a value of the intercalative binding constant comparable to that obtained by UV spectrophotometric titration. Finally, the temperature dependence of the absorbance at 258 nm shows that the metal complex strongly increases the DNA melting temperature already at metal complex-DNA molar ratio equal to 0.25 suggesting that metal complex intercalation effectively hinders DNA denaturation. Overall, the results of the present study point out that the Fe III dppz aquo complex has DNA-binding properties analogous to those previously reported for the tris-chelate Fe II (phen) 2 dppz complex (phen = 1,10-phenantroline).

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“…The same authors proved that flavonoid prooxidative properties were dose-dependent; Q was cytotoxic to most cell lines at concentrations higher than 300 mmol mL -1 (23). Transition metal complexes which are stable, inert, and could serve as probes for different biological systems (1) have become interesting as potential anticancer drugs not only because of these chemical properties, but also because of their ability to bind to DNA and induce cell death through intercalation (1,6,12). The degree of intercalation corresponds to the planarity of the ligand in a complex; the more planar a ligand the stronger the intercalation effect.…”

Section: Discussionmentioning

confidence: 99%

“…Oxidative damage of cellular lipids 1.5x10 6 cells were seeded in 10-cm Petri dishes, attached, and treated with previously determined subtoxic concentrations of Q, La, and the Q/La complex (300 mmol mL -1 , 400 mmol mL -1 , and 500 mmol mL -1 , for each) for three hours. The cells were then scraped, washed, and lysed, and the cell supernatant incubated with trichloroacetic acid, cooled, and mixed with thiobarbituric acid.…”

Section: Cell Survivalmentioning

confidence: 99%

Cytotoxic and Genotoxic Effects of the Quercetin/Lanthanum Complex on Human Cervical Carcinoma Cells In Vitro

Durgo

Halec

Šola

et al. 2011

Archives of Industrial Hygiene and Toxicology

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Quercetin is the main fl avonoid in diet with a potential in the treatment of cancer, cardiovascular, and neurodegenerative diseases. Due to its specifi c planar chemical structure, quercetin readily forms chelates with metal ions. Complexes of bioactive compounds and metal ions such as lanthanum often show strong cytotoxic and antitumour properties. The aim of this study was to compare the genotoxic effects of the quercetin/lanthanum complex on human cervical carcinoma cells with compare it to the effects of free ligands, quercetin, and lanthanum alone. The quercetin/lanthanum complex showed considerable cytotoxicity in the concentration range of (100 to 1000) mmol mL -1 and exposure time of three hours. The complex also induced a dose-dependent pro-oxidative effects and the formation of single-strand and double-strand DNA breaks. Although we obtained promising results on the cell level, future experiments should answer whether the quercetin/lanthanum complex is cancer-specific and stable enough in physiological conditions to make a potential new antitumour drug. Arh Hig Rada Toksikol 2011;62:221-227 Evidence abounds about antitumour activity of small-molecule compounds, including metal complexes with fl avonoids, which directly interact with DNA (1). Recently, much attention has also been paid to how cancer cell growth and apoptosis are affected by rare earth metals and compounds such as lanthanum and cerium salts (2, 3). KEY WORDS: chelates, DNA damage, fl avonoid/metal complexes, oxidative damage Durgo K et al. QUERCETIN/LANTHANUM COMPLEX EFFECTS ON HUMAN CERVICAL CARCINOMA CELLSLanthanum salts can arrest the cell cycle in the G1/S phase in leukemic cell lines (2) and inhibit telomerase activity in the lymphoblastoid tumour cell line (3). Both induce apoptotic events. Contrary to this effect observed in tumour cells, no effect could be determined in normal bone marrow haematopoietic cells (2). Lanthanum complexed with bioactive compounds from plants has shown even stronger cytotoxic effect than when administered alone (4), suggesting that electron transfer and oxidative stress are responsible for the cytotoxic effect. Kostova et al. (5) found that lanthanum complexes with biscoumarins caused apoptotic cell death of several leukaemia and lymphoma cell lines, causing DNA fragmentation and morphological changes. The authors believe that this cytotoxic effect depends on the metal-ligand structure. Wang et al. (1) analysed a lanthanum-naringenin Schiff-base complex and found that the ligands were coordinated to the lanthanum ion through deprotonated hydroxyl groups. This complex bound directly to calf-thymus DNA, probably through intercalation, while the same concentrations caused a strong cytotoxic effect on human leukaemia and lung adenocarcinoma cells. Intercalation is the main cytotoxic mechanism of numerous antitumour agents such as cisplatin, but their use is limited by drug resistance. Determination and synthesis of new agents

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DNA binding mode of ruthenium complexes and relationship to tumor cell toxicity

Cited by 358 publications

References 69 publications

Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

Characterization of the binding sites of the anticancer ruthenium(III) complexes KP1019 and KP1339 on human serum albumin via competition studies

The interaction of native calf thymus DNA with FeIII-dipyrido[3,2-a:2′,3′-c]phenazine

Cytotoxic and Genotoxic Effects of the Quercetin/Lanthanum Complex on Human Cervical Carcinoma Cells In Vitro

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