ATP-Binding Cassette B1 Transports Seliciclib (<i>R</i>-Roscovitine), a Cyclin-Dependent Kinase Inhibitor

Rajnai, Zsuzsanna; Méhn, Dóra; Beéry, Erzsébet; Okyar, Alper; Jani, Márton; Tóth, Gábor; Fülöp, Ferenc; Lévi, Françis; Krajcsi, Péter

doi:10.1124/dmd.110.032805

Cited by 18 publications

(14 citation statements)

References 27 publications

(36 reference statements)

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“…In agreement, several studies showed that roscovitine represents a high-affinity substrate of P-gp as well, yet no concomitant ABCB1-mediated resistance could be observed after treatment with roscovitine (26). Noteworthy, roscovitine was also shown to induce apoptosis in a doxorubicinresistant human myeloma cell line that overexpresses Pgp (37). Therefore, we speculate that despite being P-gp substrates, BA-12 and BP-14 do not induce resistance and are thus being promising novel therapeutic agents with persistent antihepatoma activities.…”

Section: Discussionsupporting

confidence: 68%

Novel Inhibitors of Cyclin-Dependent Kinases Combat Hepatocellular Carcinoma without Inducing Chemoresistance

Haider

Grubinger

Řezníčková

et al. 2013

Molecular Cancer Therapeutics

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Treatment options for hepatocellular carcinoma using chemotherapeutics at intermediate and advanced stages of disease are limited as patients most rapidly escape from therapy and succumb to disease progression. Mechanisms of the hepatic xenobiotic metabolism are mostly involved in providing chemoresistance to therapeutic compounds. Given the fact that the aberrant activation of cyclin-dependent kinases (CDK) is frequently observed in hepatocellular carcinomas, we focused on the efficacy of the novel compounds BA-12 and BP-14 that antagonize CDK1/2/5/7 and CDK9. Inhibition of those CDKs in human hepatocellular carcinoma cell lines reduced the clonogenicity by arresting cells in S-G 2 and G 2 -M phase of the cell cycle and inducing apoptosis. In contrast, primary human hepatocytes failed to show cytotoxicity and apoptosis. No loss of chemosensitivity was observed in hepatocellular carcinoma cells after long-term exposure to inhibitors. In vivo, treatment of xenografted human hepatocellular carcinomas with BA-12 or BP-14 effectively repressed tumor formation. Moreover, BA-12 or BP-14 significantly diminished diethylnitrosamine (DEN)-induced hepatoma development in mice. These data show that BA-12 or BP-14 exhibit strong antitumorigenic effects in the absence of chemoresistance, resulting in a superior efficacy compared with currently used chemotherapeutics in hepatocellular carcinomas. Mol Cancer Ther; 12(10); 1947-57. Ó2013 AACR.

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Section: Discussionsupporting

confidence: 68%

Novel Inhibitors of Cyclin-Dependent Kinases Combat Hepatocellular Carcinoma without Inducing Chemoresistance

Haider

Grubinger

Řezníčková

et al. 2013

Molecular Cancer Therapeutics

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“…A few studies used the whole set of in vitro and in vivo tools to address BBB permeability issues [52,78,79]. But only one study has been performed on a sizeable compound set [70].…”

Section: Resultsmentioning

confidence: 99%

Efflux transporters in the blood–brain interfaces –in vitroandin vivomethods and correlations

Krajcsi

Jani

Töth

et al. 2012

Expert Opinion on Drug Metabolism & Toxicology

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A more detailed validation of in vitro efflux transporter assays employing primary brain endothelial cultures is needed. This should go along with mapping uptake transporters expressed in the blood-brain interfaces. With the availability of specific inhibitors, utilization of in vivo methods such as brain microdialysis is increasing. Once transporter-humanized mice are available, we may witness a further increase in applications of in vivo methods.

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“…Росковитин (ROSC, Sigma Aldrich, США) -ингибитор циклинзависимых протеинкиназ -вносили в лунку культурального планшета в конечной концентрации 20 мкМ [10] и инкубировали в течение 18 ч при 37°C и 5% CO 2 . К интактным клеткам линии МСF-7 добавляли культуральную среду в том же объеме, что и ингибитор, и инкубировали в тех же условиях.…”

Section: описание медицинского вмешательстваunclassified

Glutathione and Glutaredoxin in Roscovitine-Mediated Inhibition of Breast Cancer Cell Proliferation

et al. 2017

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Background: Breast tumors are number one cause of cancer morbidity and mortality among women around the world, and Russia is not an exception. Many proteins that control proliferation of immortalized cells are redox-regulated, which is essential for modulating cellular proliferative activity, especially during tumor growth. Studying the role of glutaredoxin and glutathione in cell cycle phase distribution will allow not only to identify the molecular targets regulating cell proliferation, but also to develop methods of diagnosis and targeted therapy of socially sensitive diseases, including breast cancer, in the future.Aims: To evaluate the role of glutathione and glutaredoxin in the molecular mechanisms regulating MCF-7 breast cancer cell proliferation under the effects of roscovitine, a cyclin-dependent protein kinase inhibitor.Materials and methods: The MCF-7 cell line (human breast adenocarcinoma) was used in the study. The cell culture was incubated in the presence and absence of roscovitine in the final concentration of 20 µmol for 18 h. The production of reactive oxygen species, the distribution of cells between cell cycle phases and the amount of Annexin V positive cells were determined using flow cytometry. The concentrations of total, reduced and oxidized glutathione, protein SH groups and protein-bound glutathione were measured by spectrophotometry. The levels of glutaredoxin, cyclin E and cyclin-dependent protein kinases were estimated by Western blotting with monoclonal antibodies.Results: The effects of roscovitine in the MCF-7 cells resulted in cell cycle arrest in G2/М phases with the decreased levels of cyclin E and cyclin-dependent protein kinase 2. It was accompanied by activation of programmed cell death. In tumor cells incubated in the presence of roscovitine, oxidative stress was triggered, which was accompanied by the elevated generation of reactive oxygen species, the decrease in the concentration of reduced glutathione, and the rise in the level of glutaredoxin. It contributed to the increase in protein glutathionylation against the backdrop of the decreased SH group concentration.Conclusions: Breast cancer cell proliferation under the effects of roscovitine is reduced following not only the decrease in the cyclin level and cyclin-dependent protein kinase activity, but also the shift in the intracellular oxidant/antioxidant ratio. Roscovitine-induced oxidative stress in the MCF-7 cells contributed to protein glutathionylation with the changes in the protein structure and functions. It results in impaired cell cycle progression, indicating a possibility to regulate cellular proliferation through modulating functional properties of redox-dependent proteins using the glutathione/glutaredoxin system.

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ATP-Binding Cassette B1 Transports Seliciclib (R-Roscovitine), a Cyclin-Dependent Kinase Inhibitor

Cited by 18 publications

References 27 publications

Novel Inhibitors of Cyclin-Dependent Kinases Combat Hepatocellular Carcinoma without Inducing Chemoresistance

Novel Inhibitors of Cyclin-Dependent Kinases Combat Hepatocellular Carcinoma without Inducing Chemoresistance

Efflux transporters in the blood–brain interfaces –in vitroandin vivomethods and correlations

Glutathione and Glutaredoxin in Roscovitine-Mediated Inhibition of Breast Cancer Cell Proliferation

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