Ruthenium (II)-Derived Organometallic Compounds Induce Cytostatic and Cytotoxic Effects on Mammalian Cancer Cell Lines through p53-Dependent and p53-Independent Mechanisms

Gaiddon, Christian; Jeannequin, Pierre; Bischoff, Pierre; Pfeffer, Michel; Sirlin, Claude B.; Loeffler, Jean‐Philippe

doi:10.1124/jpet.105.089342

Cited by 127 publications

(105 citation statements)

References 38 publications

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“…Indeed, several ruthenium-containing drugs interact with DNA and modify its structure, suggesting that they might induce DNA damages. Activation of p53 or p73 by some of these drugs partly corroborated this hypothesis (23)(24)(25). Alternative modes of action have also been described, including production of reactive oxygen species (26), inhibition of kinases (27), modification of enzymatic activities (28), or redox reactions (29).…”

Section: Introductionmentioning

confidence: 57%

A Ruthenium-Containing Organometallic Compound Reduces Tumor Growth through Induction of the Endoplasmic Reticulum Stress GeneCHOP

et al. 2009

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Cisplatin-derived anticancer therapy has been used for three decades despite its side effects. Other types of organometallic complexes, namely, some ruthenium-derived compounds (RDC), which would display cytotoxicity through different modes of action, might represent alternative therapeutic agents. We have studied both in vitro and in vivo the biological properties of RDC11, one of the most active compounds of a new class of RDCs that contain a covalent bond between the ruthenium atom and a carbon. We showed that RDC11 inhibited the growth of various tumors implanted in mice more efficiently than cisplatin. Importantly, in striking contrast with cisplatin, RDC11 did not cause severe side effects on the liver, kidneys, or the neuronal sensory system. We analyzed the mode of action of RDC11 and showed that RDC11 interacted poorly with DNA and induced only limited DNA damages compared with cisplatin, suggesting alternative transduction pathways.

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Section: Introductionmentioning

confidence: 57%

A Ruthenium-Containing Organometallic Compound Reduces Tumor Growth through Induction of the Endoplasmic Reticulum Stress GeneCHOP

et al. 2009

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“…However, the mechanisms of action of ruthenium-based anticancer compounds are comparatively unexplored, although it is clear that ruthenium compounds interact far more weakly with DNA relative to platinum compounds [15]. There is evidence to suggest that ruthenium compounds might directly interfere with specific proteins involved in signal transduction pathways and/or alter cell adhesion and migration processes [10,16,17].…”

Section: Introductionmentioning

confidence: 99%

Exploring metallodrug–protein interactions by mass spectrometry: comparisons between platinum coordination complexes and an organometallic ruthenium compound

et al. 2009

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Electrospray ionisation mass spectrometry was used to analyse the reactions of metal compounds with mixtures of selected proteins. Three representative medicinally relevant compounds, cisplatin, transplatin and the organometallic ruthenium compound RAPTA-C, were reacted with a pool of three proteins, ubiquitin, cytochrome c and superoxide dismutase, and the reaction products were analysed using high-resolution mass spectrometry. Highly informative electrospray ionisation mass spectra were acquired following careful optimisation of the experimental conditions. The formation of metal-protein adducts was clearly observed for the three proteins. In addition, valuable information was obtained on the nature of the proteinbound metallofragments, on their distribution among the three different proteins and on the binding kinetics. The platinum compounds were less reactive and considerably less selective in protein binding than RAPTA-C, which showed a high affinity towards ubiquitin and cytochrome c, but not superoxide dismutase. In addition, competition studies between cisplatin and RAPTA-C showed that the two metallodrugs have affinities for the same amino acid residues on protein binding.

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“…11-16) Pfeffer and colleagues 17,18) and Chao and colleagues 19,20) have found that some cyclometalated ruthenium(II) complexes are good candidates for becoming anticancer drugs. A cyclometalated ruthenium fragment with a metal-carbon σ bond is a crucial element for a potential anticancer drug.…”

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confidence: 99%

“…[5][6][7][8][9][10] Several ruthenium complexes that display an activity comparable to that of cisplatin have been described, and in some cases activities are even better. [11][12][13][14][15][16] Pfeffer and colleagues 17,18) and Chao and colleagues 19,20) have found that some cyclometalated ruthenium(II) complexes are good candidates for becoming anticancer drugs. A cyclometalated ruthenium fragment with a metal-carbon σ bond is a crucial element for a potential anticancer drug.…”

mentioning

confidence: 99%

DNA Interaction and Cytotoxicity of Cyclometalated Ruthenium(II) Complexes as Potential Anticancer Drugs

Matsui

Sugiyama

Nakai

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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To evaluate the anticancer activity of the cyclometalated ruthenium(II) complexes [Ru(bpy) 2 (C^N)]Cl, we have studied the interaction of these complexes using calf thymus DNA (CT-DNA) and cytotoxicity assays with two tumor (L1210 and HeLa) and a non-tumor (BALB/3T3 clone A31) cell lines. It is suggested that the complexes act as intercalators and/or DNA minor groove binders. Moreover, the complexes display favorable cytotoxicity activities with L1210 and HeLa, which in all cases were significantly more favorable than cisplatin. In contrast, the complexes exhibit appreciably lower cytotoxicity toward BALB/3T3 clone A31.Key words cyclometalated ruthenium(II) complex; anticancer drug; cytotoxicity; oxidative DNA cleavage; lipophilicityThe discovery of cisplatin (cis-diamminedichloridoplatinum(II)) by Rosenberg was one of the most significant events for cancer chemotherapy.1) However, the use of cisplatin is restricted by its high toxicity, which leads to undesirable side effects and incidents of drug resistance. With the aim of overcoming these limitations, new platinum-based and non-platinum anticancer drugs are under development. A relatively new line of investigation focuses on ruthenium chemistry in an alternative metallopharmaceutical approach to platinum.2,3) The higher coordination number of ruthenium compared with platinum provides additional coordination sites, which can potentially be used to fine-tune the properties of the complex, for example, by influencing the way the complex interacts with DNA. 4)It is well accepted that ruthenium complexes can display anticancer effects with a fairly high selectivity, the lethality of the tumor cells being higher than that of the normal cells.5-10) Several ruthenium complexes that display an activity comparable to that of cisplatin have been described, and in some cases activities are even better.11-16) Pfeffer and colleagues 17,18) and Chao and colleagues 19,20) have found that some cyclometalated ruthenium(II) complexes are good candidates for becoming anticancer drugs. A cyclometalated ruthenium fragment with a metal-carbon σ bond is a crucial element for a potential anticancer drug. The ruthenium-carbon bond is known to lower the redox potential of ruthenium(III/II) couple dramatically, so that cyclometalated ruthenium(II) complexes may serve as good catalysts for the generation of hydroxyl radicals by virtue of the Fenton-like reaction. In addition, they have good lipophilicity that allows their entries into the cells. 18,20) From two features these cyclometalated ruthenium(II) complexes may lead to excellent anticancer drugs because many cancer cells possess low levels of catalase activity. 21)In the present study, we have synthesized the cyclometalated ruthenium(II) complexes as shown in Fig. 1, [Ru(bpy) 2 (C^N)] Cl, where bpy is 2,2′-bipyridine and C^N is the deprotonated cyclometalating ligand (2-phenylpyridine (phpy), 2-(4-methylphenyl) pyridine (mphpy), or diphenyldiazene (dphdaz)). To evaluate the anticancer activity of these complexes physicochemical p...

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Ruthenium (II)-Derived Organometallic Compounds Induce Cytostatic and Cytotoxic Effects on Mammalian Cancer Cell Lines through p53-Dependent and p53-Independent Mechanisms

Cited by 127 publications

References 38 publications

A Ruthenium-Containing Organometallic Compound Reduces Tumor Growth through Induction of the Endoplasmic Reticulum Stress GeneCHOP

A Ruthenium-Containing Organometallic Compound Reduces Tumor Growth through Induction of the Endoplasmic Reticulum Stress GeneCHOP

Exploring metallodrug–protein interactions by mass spectrometry: comparisons between platinum coordination complexes and an organometallic ruthenium compound

DNA Interaction and Cytotoxicity of Cyclometalated Ruthenium(II) Complexes as Potential Anticancer Drugs

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