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  • 1
    Language: English
    In: PLoS ONE, 01 January 2016, Vol.11(9), p.e0162916
    Description: Valproic acid (VPA) is a well-known antiepileptic drug that exhibits antitumor activities through its action as a histone deacetylase inhibitor. CD133 is considered to be a cancer stem cell marker in several tumors including neuroblastoma. CD133 transcription is strictly regulated by epigenetic modifications. We evaluated the epigenetic effects of treatment with 1mM VPA and its influence on the expression of CD133 in four human neuroblastoma cell lines. Chemoresistance and cell cycle of CD133+ and CD133- populations were examined by flow cytometry. We performed bisulfite conversion followed by methylation-sensitive high resolution melting analysis to assess the methylation status of CD133 promoters P1 and P3. Our results revealed that VPA induced CD133 expression that was associated with increased acetylation of histones H3 and H4. On treatment with VPA and cytostatics, CD133+ cells were mainly detected in the S and G2/M phases of the cell cycle and they showed less activated caspase-3 compared to CD133- cells. UKF-NB-3 neuroblastoma cells which express CD133 displayed higher colony and neurosphere formation capacities when treated with VPA, unlike IMR-32 which lacks for CD133 protein. Induction of CD133 in UKF-NB-3 was associated with increased expression of phosphorylated Akt and pluripotency transcription factors Nanog, Oct-4 and Sox2. VPA did not induce CD133 expression in cell lines with methylated P1 and P3 promoters, where the CD133 protein was not detected. Applying the demethylating agent 5-aza-2'-deoxycytidine to the cell lines with methylated promoters resulted in CD133 re-expression that was associated with a drop in P1 and P3 methylation level. In conclusion, CD133 expression in neuroblastoma can be regulated by histone acetylation and/or methylation of its CpG promoters. VPA can induce CD133+ cells which display high proliferation potential and low sensitivity to cytostatics in neuroblastoma. These results give new insight into the possible limitations to use VPA in cancer therapy.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 2
    Language: English
    In: Journal of Controlled Release, 10 July 2016, Vol.233, pp.136-146
    Description: Water-soluble -(2-hydroxypropyl)methacrylamide copolymer conjugates bearing the anticancer drugs doxorubicin (Dox) or pirarubicin (THP), P-gp inhibitors derived from reversin 121 (REV) or ritonavir (RIT)), or both anticancer drug and P-gp inhibitor were designed and synthesized. All biologically active molecules were attached to the polymer carrier pH-sensitive spacer enabling controlled release in mild acidic environment modeling endosomes and lysosomes of tumor cells. The cytotoxicity of the conjugates against three sensitive and Dox-resistant neuroblastoma (NB) cell lines, applied alone or in combination, was studied . All conjugates containing THP displayed higher cytotoxicity against all three Dox-resistant NB cell lines compared with the corresponding Dox-containing conjugates. Furthermore, the cytotoxicity of conjugates containing both drug and P-gp inhibitor was up to 10 times higher than that of the conjugate containing only drug. In general, the polymer-drug conjugates showed higher cytotoxicity when conjugates containing inhibitors were added 8 or 16 h prior to treatment compared with conjugates bearing both the inhibitor and the drug. The difference in cytotoxicity was more pronounced at the 16-h time point. Moreover, higher inhibitor:drug ratios resulted in higher cytotoxicity. The cytotoxicity of the polymer-drug used in combination with polymer P-gp inhibitor was up to 84 times higher than that of the polymer-drug alone.
    Keywords: N-(2-Hydroxypropyl)Methacrylamide Copolymers ; Multidrug Resistance ; P-Glycoprotein Inhibitors ; Reversin 121 ; Ritonavir ; Doxorubicin ; Pirarubicin ; Neuroblastoma ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0168-3659
    E-ISSN: 1873-4995
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  • 3
    In: ELECTROPHORESIS, June 2013, Vol.34(11), pp.1637-1648
    Description: In this study, we determined serum levels of metallothioneins (s) and zinc in children with solid tumours (neuroblastoma, Hodgkin lymphoma, medulloblastoma, osteosarcoma, Ewing sarcoma and nephroblastoma) by differential pulse voltammetry Brdicka reaction and . n(II) level in patients sera was 40% compared to controls, contrariwise, level was 4.2 × higher in patients. No significant differences among single diagnoses were found both for n(II) and . When determined n(II)/ ratio, in controls its value was 24.6, but it was 2.6 in patients. After estern‐blotting with anti‐ and anti‐n chicken antibodies, variable intensities of the bands within the samples were observed. The brightness curve obtained for each sample both for ‐ and n blots was further analysed to produce a list of band positions together with some complementary information related to the intensity of the observed bands by the optimised algorithm. We constructed from those profiles decision trees that enable to distinguish different groups of tumours. The blood samples were heat‐treated, in which we supposed mainly , but samples contained other thermostable n‐containing proteins that were helpful for identification of embryonal tumours with 88% accuracy and for identification of sarcomas with 78% accuracy. In blots the accuracies were 53 and 45%, respectively. Simultaneous analysis of and n blots did not increased accuracy of identification neither in embryonal tumours (80%) nor in sarcomas. Those results are promising not only from diagnostic point of view but particularly in the area of studying of individual isoforms and their aggregates in malignant tumours.
    Keywords: Cancer ; Metallothionein ; Signal Processing ; Zinc
    ISSN: 0173-0835
    E-ISSN: 1522-2683
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  • 4
    Language: English
    In: International Journal of Oncology, Vol.47(1), pp.343-352
    Description: High-risk neuroblastoma remains one of the most important therapeutic challenges for pediatric oncologists. New agents or regimens are urgently needed to improve the treatment outcome of this fatal tumor. We examined the effect of histone deacetylase (HDAC) inhibitors in a combination with other chemotherapeutics on a high-risk neuroblastoma UKF-NB-4 cell line. Treatment of UKF-NB-4 cells with DNA-damaging chemotherapeutics cisplatin or etoposide combined with the HDAC inhibitor valproate (VPA) resulted in the synergistic antitumor effect. This was associated with caspase-3-dependent induction of apoptosis. Another HDAC inhibitor trichostatin A and a derivative of VPA that does not exhibit HDAC inhibitory activity, valpromide, lacked this effect. The synergism was only induced when VPA was combined with cytostatics targeted to cellular DNA; VPA does not potentiate the cytotoxicity of the anticancer drug vincristine that acts by a mechanism different from that of DNA damage. The VPA-mediated sensitization of UKF-NB-4 cells to cisplatin or etoposide was dependent on the sequence of drug administration; the potentiating effect was only produced either by simultaneous treatment with these drugs or when the cells were pretreated with cisplatin or etoposide before their exposure to VPA. The synergistic effects of VPA with cisplatin or etoposide were associated with changes in the acetylation status of histones H3 and H4. The results of this study provide a rationale for clinical evaluation of the combination of VPA and cisplatin or etoposide for treating children suffering from high-risk neuroblastoma.
    Keywords: Neuroblastoma ; Cisplatin ; Etoposide ; Valproate ; Acetylation Of Histones ; Apoptosis
    ISSN: 1019-6439
    E-ISSN: 1791-2423
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  • 5
    Language: English
    In: Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia, June 2015, Vol.159(2), pp.166-77
    Description: The aim of this review is to provide the information about molecular basis of hypoxia-induced chemoresistance, focusing on the possibility of diagnostic and therapeutic use. Hypoxia is a common feature of tumors and represents an independent prognostic factor in many cancers. It is the result of imbalances in the intake and consumption of oxygen caused by abnormal vessels in the tumor and the rapid proliferation of cancer cells. Hypoxia-induced resistance to cisplatin, doxorubicin, etoposide, melphalan, 5-flouoruracil, gemcitabine, and docetaxel has been reported in a number of experiments. Adaptation of tumor cells to hypoxia has important biological effects. The most studied factor responsible for these effects is hypoxia-inducible factor-1 (HIF-1) that significantly contributes to the aggressiveness and chemoresistance of different tumors. The HIF-1 complex, induced by hypoxia, binds to target genes, thereby increasing the expression of many genes. In addition, the expression of hundreds of genes can be also decreased in response to hypoxia in HIF-1 dependent manner, but without the detection of HIF-1 in these genes' promoters. HIF-1 independent mechanisms for drug resistance in hypoxia have been described, however, they are still rarely reported. The first clinical studies focusing on diagnosis of hypoxia and on inhibition of hypoxia-induced changes in cancer cells are starting to yield results. The adaptation to hypoxia requires many genetic and biochemical responses that regulate one another. Hypoxia-induced resistance is a very complex field and we still know very little about it. Different approaches to circumvent hypoxia in tumors are under development.
    Keywords: Hif-1 ; Chemoresistance ; Hypoxia ; Hypoxia-Induced Chemoresistance ; Drug Resistance, Neoplasm -- Physiology ; Hypoxia-Inducible Factor 1, Alpha Subunit -- Physiology ; Neoplasms -- Drug Therapy ; Tumor Hypoxia -- Physiology
    ISSN: 1213-8118
    E-ISSN: 18047521
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  • 6
    Language: English
    In: International Journal of Molecular Sciences, 01 July 2017, Vol.18(7), p.1414
    Description: Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.
    Keywords: Histone Deacetylases ; Histone Deacetylase Inhibitors ; Cancer ; Apoptosis ; Autophagy ; Cell Cycle Arrest ; Anti-Angiogenic Effect ; Drug Combinations ; Biology
    E-ISSN: 1422-0067
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  • 7
    Language: English
    In: Pharmacology and Therapeutics, 2012, Vol.133(1), pp.26-39
    Description: Over the past forty years, anthracyclines and ellipticines have attracted attention as promising cytostatics. In this review, we focus on their mechanisms of cytoxicity, DNA-damaging effects and adverse side-effects. We also summarize ways to enhance the therapeutic effects of these drugs together with a decrease in their adverse effects. Current drug design strategies are focused on drug bioavailability and their tissue targeting, whereas drug delivery to specific intracellular compartments is rarely addressed. Therefore, therapies utilizing the antineoplastic activities of anthracyclines and ellipticines combined with novel strategies such as nanotechnologies for safer drug delivery, as well as strategies based on gene therapy, could significantly contribute to medical practice.
    Keywords: Anthracyclines ; Ellipticine ; Adduct Formation ; Nanocarriers ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0163-7258
    E-ISSN: 1879-016X
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  • 8
    Language: English
    In: Journal of Molecular Medicine, 2016, Vol.94(11), pp.1199-1215
    Description: Zinc ions are essential cofactors of a wide range of enzymes, transcription factors, and other regulatory proteins. Moreover, zinc is also involved in cellular signaling and enzymes inhibition. Zinc dysregulation, deficiency, over-supply, and imbalance in zinc ion transporters regulation are connected with various diseases including cancer. A zinc ion pool is maintained by two types of proteins: (i) zinc-binding proteins, which act as a buffer and intracellular donors of zinc and (ii) zinc transporters responsible for zinc fluxes into/from cells and organelles. The decreased serum zinc ion levels have been identified in patients suffering from various cancer diseases, including head and neck tumors and breast, prostate, liver, and lung cancer. On the contrary, increased zinc ion levels have been found in breast cancer and other malignant tissues. Zinc metalloproteomes of a majority of tumors including brain ones are still not yet fully understood. Current knowledge show that zinc ion levels and detection of certain zinc-containing proteins may be utilized for diagnostic and prognostic purposes. In addition, these proteins can also be promising therapeutic targets. The aim of the present work is an overview of the importance of zinc ions, zinc transporters, and zinc-containing proteins in brain tumors, which are, after leukemia, the second most common type of childhood cancer and the second leading cause of death in children after accidents.
    Keywords: Cancer ; Childhood brain tumors ; Metallothioneins ; Zinc metalloenzymes ; Zinc transporters
    ISSN: 0946-2716
    E-ISSN: 1432-1440
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  • 9
    Language: English
    In: Anti-Cancer Agents in Medicinal Chemistry, 2016, Vol.16(6), p.686-698
    Description: The history of metal based cytostatics began in the 1970s by discovering the effects of cisplatin. Since then several generations of platinum based cytostatics have started to be the key weapon against tumor development and metastasis occurrence. Nevertheless, some attention has been also paid to non-platinum metals, such as ruthenium, titanium, gallium, iron, cobalt, gold, and palladium. Ruthenium, titanium, and gallium complexes have been also tested in clinical studies. This boom in metal based cytostatics can be explained by great effort paid to the elucidation of mechanisms of tumor resistance to these drugs. The known mechanisms of drug resistance are: (i) down regulation, over-expression, or modification of molecules of interest; (ii) increased drug efflux; (iii) induction of anti-apoptotic mechanisms or inactivation of pro-apoptotic mechanisms; (iv) changes in enzymes with an ability to activate or detoxify a drug; (v) low access of the drug to a tumor; and/or (vi) alteration in drug metabolism or excretion [1]. Often discussed but not largely reviewed and summarized is the intracellular inactivation of platinum drugs by coordination to thiol containing biomolecules glutathione (GSH) and metallothioneins (MTs). Overexpression of MT and/or GSH may cause resistance to anticancer drugs. Thus, greater attention should be paid to these interactions in case to overcome the resistance of tumor to cytostatics.
    Keywords: Metal-Containing Cytostatic Drugs Platinum Resistance Chemoresistance Glutathione Metallothioneins.
    ISSN: 1871-5206
    E-ISSN: 1875-5992
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  • 10
    Language: English
    In: Neuro endocrinology letters, 2012, Vol.33 Suppl 3, pp.16-24
    Description: Etoposide (Vepesid, VP-16), an inhibitor of topoisomerase II, is a chemotherapeutic drug commonly used for treatment of different types of malignant diseases. By inhibiting the topoisomerase II enzyme activity in cancer cells, this drug leads to DNA damage and subsequently to cell death. In this study, we investigated the effect of this anticancer drug alone and in combination with a histone deacetylase (HDAC) inhibitor, valproic acid (VPA), on a human UKF-NB-4 neuroblastoma cell line. The effects of etoposide and VPA on UKF-NB-4 cells were tested under the normoxic and also the hypoxic (1% O2) cultivation conditions. The cytotoxicity of etoposide and VPA to a UKF-NB-4 neuroblastoma cell line was evaluated with MTT assay. Apoptosis of the cells was analyzed by flow cytometry using an Annexin V and propidium iodide binding method. The effect of etoposide and VPA on the cell cycle distribution was determined by flow cytometric analysis using propidium iodide staining. The results of the study demonstrate that UKF-NB-4 neuroblastoma cells are sensitive both to etoposide and to VPA. They also indicate that the impact of VPA on cytotoxicity of etoposide in these tumor cells varies depending on the sequence of cultivation of the cells with the drugs. As a suitable sequence of cultivation, with a high rate of suppression of neuroblastoma cell growth was found the preincubation of the cells with etoposide, which was followed by their cultivation with VPA. In contrast, the reversed combination (preincubation of the cells with VPA before their treating with etoposide) did not give any increase in etoposide cytotoxicity. The effect of such combined treatment can be explained by measuring the cell cycle distribution, which shows that both etoposide and VPA change the cell cycle phase distribution. Etoposide and VPA were found as cycle phase specific drugs that are cytotoxic to human UKF-NB-4 neuroblastoma cells used either as single drugs or both together. However, whereas VPA might sensitize the cells to etoposide, inappropriate sequence of cultivation of the cells with VPA can decrease the etoposide cytotoxic efficacy. The results found here warrant further studies of combined treatment of neuroblastoma cells with etoposide with HDAC inhibitors and may help in the design of new protocols geared to the treatment of high risk neuroblastomas.
    Keywords: Bone Marrow Neoplasms -- Drug Therapy ; Brain Neoplasms -- Drug Therapy ; Etoposide -- Pharmacology ; Neuroblastoma -- Drug Therapy ; Valproic Acid -- Pharmacology
    ISSN: 0172-780X
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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