Inhibition of the MEK/ERK signaling pathway by the novel antimetastatic agent NAMI‐A down regulates c‐<i>myc</i>gene expression and endothelial cell proliferation

Pintus, Gianfranco; Tadolini, Bruna; Posadino, Anna Maria; Sanna, Bastiano; Debidda, Marcella; Bennardini, Federico; Sava, Gianni; Ventura, Carlo

doi:10.1046/j.1432-1033.2002.03307.x

Cited by 71 publications

(39 citation statements)

References 32 publications

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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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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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“…One possible explanation raised from our results is that atorvastatin induces changes in protein prenylation and in the phosphoprotein signature associated with the inhibition of several signaling pathways, such as Ras and ERK1/2, that are thought to be required for MYC phosphorylation and activation ( Figure S7). [73][74][75] Atorvastatin caused the dephosphorylation and inactivation of MYC, which in turn was assossciated with the suppression of the expression of MYC target genes. Atorvastatin's effects on the phosphorylation state of MYC were specific to the inhibition of HMGcoA reductase, as treatment with mevalonate abrogated these effects and the ability of atorvastatin to reverse or suppress tumorigenesis.…”

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confidence: 99%

Inhibition of HMGcoA reductase by atorvastatin prevents and reverses MYC-induced lymphomagenesis

Shachaf

Perez

Youssef

et al. 2007

Blood

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Statins are a class of drugs that inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMGcoA) reductase, a critical enzyme in the mevalonate pathway. Several reports document that statins may prevent different human cancers. However, whether or not statins can prevent cancer is controversial due to discordant results. One possible explanation for these conflicting conclusions is that only some tumors or specific statins may be effective. Here, we demonstrate in an in vivo transgenic model in which atorvastatin reverses and prevents the onset of MYC-induced lymphomagenesis, but fails to reverse or prevent tumorigenesis in the presence of constitutively activated K-Ras (G12D). Using phosphoprotein fluorescence-activated cell sorter (FACS) analysis, atorvastatin treatment was found to result in the inactivation of the Ras and ERK1/2 signaling pathways associated with the dephosphorylation and inactivation of MYC. Correspondingly, tumors with a constitutively activated K-Ras (G12D) did not exhibit dephosphorylation of ERK1/2 and MYC. Atorvastatin's effects on MYC were specific to the inhibition of HMGcoA reductase, as treatment with mevalonate, the product of HMG-CoA reductase activity, abrogated these effects and inhibited the ability of atorvastatin to reverse or suppress tumorigenesis. Also, RNAi directed at HMGcoA reductase was sufficient to abrogate the neoplastic properties of MYC-induced tumors. IntroductionCancer is largely caused by genomic events which result in the activation of oncogenes or the loss of tumor-suppressor genes. 1 The targeted inactivation of oncogenes may be a specific and effective therapy for treating certain malignancies. 2,3 Experimental results in animal models validate the notion that the targeted inactivation of a single oncogene can be sufficient to reverse tumorigenesis. 4 Drugs that target specific proteins have been identified and shown to be effective in the treatment of certain cancers, [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] which indicates that some neoplasms are susceptible to therapies that target their molecular causes. However, cancers can escape dependence upon oncogenes, as observed in animal models as well as in human patients. [21][22][23] Thus, the best targets may not be the suspected oncogenes but rather proteins essential to multiple signaling or metabolic pathways required for tumor maintenance.MYC is one of the oncogenes most commonly associated with human cancer. 24 Experimentally, the inactivation of MYC has been shown to induce sustained tumor regression in transgenic mouse models of many different tumors, suggesting that MYC may be a good target for cancer treatment. [25][26][27][28] However, MYC as a transcription factor is not easy to target directly with small molecules. Thus, rather than directly targeting MYC, it might be possible to inactivate MYC through the disruption of upstream regulatory signaling molecules such as those in pathways regulated by Ras and ERK1/2. 29,30 The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMGcoA) r...

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“…NAMI-A, for example, significantly reduces cdk1 at doses active on cell proliferation (Pintus et al, 2002) in ECV304 endothelial cells. In this study, we extended the examination to cdk2 kinase, involved in the S phase (Reed, 1997), to p27, an inhibitor of cell progression among cell cycle phases (Polyak et al, 1994), and to nuclear proliferation antigen PCNA, whose expression levels are related and proportional to cell proliferation (Kurki et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

Distinct Effects of Dinuclear Ruthenium(III) Complexes on Cell Proliferation and on Cell Cycle Regulation in Human and Murine Tumor Cell Lines

Bergamo¹,

Stocco²,

Gava³

et al. 2003

J Pharmacol Exp Ther

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We have examined the biological and antitumor activity of a series of dinuclear ruthenium complexes. The aim of this study was to compare the in vitro effects of these new compounds on cell proliferation, cell distribution among cell cycle phases, and the expression of some proteins involved in cell cycle regulation. Results obtained show a mild cytotoxic activity against human and murine cell lines, more evident after prolonged exposure of cell challenge. Two of the eight dinuclear complexes [namely, compounds D3 (Na 2 [{RuCl 4 (dmso-S)} 2 (-bipy)]) and D7 ([NH 4 ][{RuCl 4 (dmso-S)}(-pyz){RuCl 3 (dmso-S)(dmso-O)}]) modify cell cycle distribution similarly to imidazolium trans-imidazoledimethylsulfoxidetetrachlororuthenate (NAMI-A), whereas the others have a low or negligible effect on this parameter. If we correlate the induction of cell cycle modifications with ruthenium uptake by tumor cells and with the modulation of proteins regulating cell cycle, we may stress that the induction of G 2 -M cell cycle arrest is related to the achievement of a threshold concentration of ruthenium inside the cells, which is dependent on the cell line being used, and that only cyclin B, among cell cycle regulating proteins examined by immunoblotting assays, appears to be significantly modified. This in vitro study shows that dinuclear ruthenium complexes may have a behavior similar to that of the monomer NAMI-A. These results encourage the future experimentation of their pharmacological properties in in vivo models.The study of the pharmacological properties of ruthenium compounds led to the identification of the potent antitumor activity of compounds with ammine, heterocyclic, and sulfoxide ligands (Keppler and Rupp, 1986;Keppler et al., 1987;Clarke et al., 1988;Clarke, 1989;Sava et al., 1992Sava et al., , 1998Sava et al., , 1999. Among these latter, NAMI-A (ImH[trans-RuCl 4 (dmso-S)Im]; Im ϭ imidazole, dmso-S ϭ S-bonded dimethyl sulfoxide) proved to be particularly effective against spontaneous metastases of experimental tumors with an activity that is accompanied only by a mild or absent reduction of the primary tumors of the treated animals (Sava et al., 1998). One important property of NAMI-A is the capacity to inhibit the growth of already established metastases in addition to the prevention of metastasis formation . Although NAMI-A and cisplatin are both based on a group VIII transition metal, the antitumor activity of the ruthenium complex, unrelated to a direct cytotoxic mechanism, is quite different from that of cisplatin. Among platinum compounds, a significant therapeutic advancement is given by multinuclear compounds that highlight the possibility of overcoming the problem of resistance, since they increase the interchain DNA binding, which is more refractory to cell repair systems (Farrell et al., 1999).Although the activity of NAMI-A and related compounds on DNA and/or other related molecules still has not been clarified, we thought it worthwhile to test the pharmacological properties of a new series of ...

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Inhibition of the MEK/ERK signaling pathway by the novel antimetastatic agent NAMI‐A down regulates c‐mycgene expression and endothelial cell proliferation

Cited by 71 publications

References 32 publications

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

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

Inhibition of HMGcoA reductase by atorvastatin prevents and reverses MYC-induced lymphomagenesis

Distinct Effects of Dinuclear Ruthenium(III) Complexes on Cell Proliferation and on Cell Cycle Regulation in Human and Murine Tumor Cell Lines

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