Intrinsic and Acquired Forms of Resistance against the Anticancer Ruthenium Compound KP1019 [Indazolium<i>trans</i>-[tetrachlorobis(1<i>H</i>-indazole)ruthenate (III)] (FFC14A)

Heffeter, Petra; Pongratz, M.; Steiner, Elisabeth; Chiba, Peter; Jakupec, Michael A.; Elbling, Leonilla; Marian, Brigitte; Körner, Wilfried; Sevelda, Florian; Micksche, M.; Keppler, Bernhard K.; Berger, Walter

doi:10.1124/jpet.104.073395

Cited by 77 publications

(80 citation statements)

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“…1 and 2 show that KP1019 exerts both cytotoxic and cytostatic effects on yeast. Although the concentration of KP1019 that kills approximately 50% of wild-type yeast (163mg/ml or 273mM) is somewhat higher than the IC 50 values (56-179mM) reported for cancer cells in vitro (Heffeter et al, 2005;Heffeter et al, 2010), this result is not surprising given that yeast often display higher levels of resistance to antineoplastic agents (Stepanov et al, 2008).…”

Section: Discussionmentioning

confidence: 77%

“…One intriguing feature of KP1019 is that it maintains potency against many drug-resistant cell lines (Heffeter et al, 2005). To determine whether this feature is conserved between yeast and mammalian cells, we examined the ability of KP1019 to inhibit growth of yeast carrying mutations in the PDR network.…”

Section: Discussionmentioning

confidence: 99%

“…Since KP1019 maintains potency against multidrug resistant (MDR) cancer cell lines (Heffeter et al, 2005), we wanted to establish whether KP1019 functions similarly when applied to S. cerevisiae exhibiting pleiotropic drug resistance (PDR), the yeast analog of MDR. In yeast, PDR is controlled primarily by two transcription activators, Pdr1 and Pdr3 (reviewed in Balzi and Goffeau, 1995;Moye-Rowley, 2003).…”

Section: Kp1019 Is Internalized By and Kills Yeastmentioning

confidence: 99%

“…Preliminary studies also suggest that KP1019 might be promising in the treatment of drug-resistant tumors, as it remains effective against cancer cell lines that are highly resistant to other chemotherapeutic agents. Specifically, cell lines resistant to doxorubicin and adriamycin remain sensitive to the effects of KP1019 (Heffeter et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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The Anticancer Ruthenium Complex KP1019 Induces DNA Damage, Leading to Cell Cycle Delay and Cell Death inSaccharomyces cerevisiae

et al. 2012

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The anticancer ruthenium complex trans-[tetrachlorobis(1H-indazole)ruthenate(III)], otherwise known as KP1019, has previously been shown to inhibit proliferation of ovarian tumor cells, induce DNA damage and apoptosis in colon carcinoma cells, and reduce tumor size in animal models. Notably, no doselimiting toxicity was observed in a Phase I clinical trial. Despite these successes, KP1019's precise mechanism of action remains poorly understood. To determine whether Saccharomyces cerevisiae might serve as an effective model for characterizing the cellular response to KP1019, we first confirmed that this drug is internalized by yeast and induces mutations, cell cycle delay, and cell death. We next examined KP1019 sensitivity of strains defective in DNA repair, ultimately showing that rad1D, rev3D, and rad52D yeast are hypersensitive to KP1019, suggesting that nucleotide excision repair (NER), translesion synthesis (TLS), and recombination each play a role in drug tolerance. These data are consistent with published work showing that KP1019 causes interstrand cross-links and bulky DNA adducts in mammalian cell lines. Published research also showed that mammalian cell lines resistant to other chemotherapeutic agents exhibit only modest resistance, and sometimes hypersensitivity, to KP1019. Here we report similar findings for S. cerevisiae. Whereas gain-of-function mutations in the transcription activator-encoding gene PDR1 are known to increase expression of drug pumps, causing resistance to structurally diverse toxins, we now demonstrate that KP1019 retains its potency against yeast carrying the hypermorphic alleles PDR1-11 or PDR1-3. Combined, these data suggest that S. cerevisiae could serve as an effective model system for identifying evolutionarily conserved modulators of KP1019 sensitivity.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Kp1019 Is Internalized By and Kills Yeastmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Anticancer Ruthenium Complex KP1019 Induces DNA Damage, Leading to Cell Cycle Delay and Cell Death inSaccharomyces cerevisiae

et al. 2012

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“…Clearly, ruthenium complexes represent a new class of compounds endowed with antitumor activity (1,22). Two ruthenium complexes NAMI-A and KP1019 are already in clinical trials (23)(24)(25)(26)(27). Ruthenium complexes are rich in chemistry and the side-effects of the ruthenium complexes are low compared to platinum-derived drugs because of the selective activation to cytotoxic species in solid tumor tissues (28).…”

Section: Introductionmentioning

confidence: 99%

Anticancer activities of the ruthenium carboxylato, amido and pyridine complexes

Srivastava

Fronczek²,

Perkins³

et al. 2010

Int J Oncol

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Abstract. Ruthenium complexes [1][2][3] with oxalato, amido and pyridine ligands have been synthesized and characterized. Biological tests showed that the ruthenium complexes 2 and 3 have modest cytotoxicity on both murine cell line NIH3T3 and human cancer colon cell lines HCT116 and HT29 while complex 1 has no obvious growth defect. We further tested why complexes 2 and 3 exhibit modest cytotoxicity. Gel electrophoresis analysis demonstrates that complex 3 has the ability to cleave double-stranded DNAs in a dose-dependent manner. In contrast, complex 2 does not have detectable DNA cleavage activity. Additionally, real-time PCR analysis suggests that the observed cell growth inhibition or death could be due to the altered gene expression in the processes of cell cycle and apoptosis/necrosis caused by the addition of complexes 2 and 3. Furthermore, cell death by DNA fragmentation assay indicates that the addition of these two complexes may cause cell necrosis rather than apoptosis.

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Ruthenium, Titanium and Gallium for Treating Cancer

Dabrowiak

2009

Metals in Medicine

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Complexes of ruthenium, Ru, which have been extensively used as metal catalysts for chemical transformations, are also showing considerable promise for the treatment of cancer [1][2][3][4][5][6]. While some of these agents directly attack and kill the primary tumor, others have the interesting property of preventing the tumor from releasing cells that spread to other parts of the body. The structures and properties of these compounds range from traditional coordination compounds that lose ligands by interacting directly with biological targets to organometallic compounds which, in addition to binding to molecular targets, can facilitate the generation of reactive oxygen species, ROSs, which chemically modify biological molecules in the cell. In addition to killing cells through chemical reactivity, some ruthenium compounds express their biological effects by acting as shape-specific inhibitors of enzymes that are important for the survival of the cell. A brief overview of the chemistry and mechanistic aspects of these compounds will be given in this chapter. Chemistry of ruthenium in the biological milieuRuthenium, atomic number 44, has a number of known oxidation states, but only two, Ru þ2 [Kr]4d 6 , a soft acid, and Ru þ3 [Kr]4d 5 , an intermediate acid, have been extensively incorporated into new agents for the treatment of cancer. Both oxidation states prefer six-coordinate octahedral geometry, with the complexes of Ru þ3 , due to its greater charge, having the higher value of CFSE, D. Since ruthenium is in the second-row transition metal series, below iron in the periodic table, most Ru þ3 , t 5 2g , S ¼ 1 / 2 , as well as Ru þ2 , t 6 2g , S ¼ 0, complexes are low-spin. The first-order water exchange rate constants, k, for aquated Ru þ2 and Ru þ3 are $10 À2 (t 1/2 $ 1 minute) and $10 À6 s À1 (t 1/2 $19 hours), respectively, at 25 C (Figure 1.20), with the exchange mechanism most likely being associative (1.23) [7]. As expected, the ion with the higher charge, which has the higher value of D, and thus the greater free energy of activation, DG z , has the smaller exchange rate constant, k, through (1.22). While the exchange rate for aquated Ru þ3 is too slow for reaction of the ion with biological targets, the exchange rate constant of Ru þ2 is about an order of magnitude larger than that of Pt þ2 , suggesting that complexes of Ru þ2 may be better suited for reaction with biological targets in the body. However, as will be evident below, exchange rates for either ion can Metals in MedicineJames C. Dabrowiak vary considerably depending on the nature of the attached ligands. An additional interesting aspect of ruthenium chemistry is that it appears that the two ruthenium oxidation states can be interconverted by substances in the body, suggesting that redox may play an important role in the pharmacology of ruthenium [5]. Although Ru þ4 has been proposed as an intermediate in the reaction of certain Ru þ3 complexes, the tetravalent oxidation state of the metal has been relatively little studied in connection wit...

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Intrinsic and Acquired Forms of Resistance against the Anticancer Ruthenium Compound KP1019 [Indazoliumtrans-[tetrachlorobis(1H-indazole)ruthenate (III)] (FFC14A)

Cited by 77 publications

References 35 publications

The Anticancer Ruthenium Complex KP1019 Induces DNA Damage, Leading to Cell Cycle Delay and Cell Death inSaccharomyces cerevisiae

The Anticancer Ruthenium Complex KP1019 Induces DNA Damage, Leading to Cell Cycle Delay and Cell Death inSaccharomyces cerevisiae

Anticancer activities of the ruthenium carboxylato, amido and pyridine complexes

Ruthenium, Titanium and Gallium for Treating Cancer

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