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Berlin Brandenburg

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  • 2014  (11)
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  • 2014  (11)
  • 1
    Description: PURPOSE: The prominent ATP-binding cassette (ABC) transporters ABCB1, ABCC1, and ABCG2 are involved in substance transport across physiological barriers and therefore in drug absorption, distribution, and elimination. They also mediate multi-drug resistance in cancer cells. Different flavonoids are known to interfere with different ABC transporters. Here, the effect of the furanoflavonol karanjin, a potential drug with antiglycaemic, gastroprotective, antifungal, and antibacterial effects, was investigated on ABCB1, ABCC1, and ABCG2-mediated drug transport in comparison to the flavonoids apigenin, genistein, and naringenin.METHODS: Cells expressing the relevant transporters (ABCB1: UKF-NB-3(ABCB1), UKF-NB-3(r)VCR¹⁰; ABCC1: G62, PC-3(r)VCR²⁰; ABCG2: UKF-NB-3(ABCG2)) were used in combination with specific fluorescent and cytotoxic ABC transporter substrates and ABC transporter inhibitors to study ABC transporter function. Moreover, the effects of the investigated flavonoids were determined on the ABC transporter ATPase activities.RESULTS: Karanjin interfered with drug efflux mediated by ABCB1, ABCC1, and ABCG2 and enhanced the ATPase activity of all three transporters. Moreover, karanjin exerted more pronounced effects than the control flavonoids apigenin, genistein, and naringenin on all three transporters. Most notably, karanjin interfered with ABCB1 at low concentrations being about 1 µM.CONCLUSIONS: Taken together, these findings should be taken into account during further consideration of karanjin as a potential drug for different therapeutic indications. The effects on ABCB1, ABCC1, and ABCG2 may affect the pharmacokinetics of co-administered drugs.
    Keywords: Pharmacy, Therapeutics, & Pharmacology;
    ISSN: 14821826
    E-ISSN: 14821826
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  • 2
    Language: English
    In: PLoS ONE, 01 January 2014, Vol.9(9), p.e108758
    Description: Aurora kinase inhibitors displayed activity in pre-clinical neuroblastoma models. Here, we studied the effects of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) and the aurora kinase inhibitor alisertib (MLN8237) that shows some specificity for aurora kinase A over aurora kinase B in a panel of neuroblastoma cell lines with acquired drug resistance. Both compounds displayed anti-neuroblastoma activity in the nanomolar range. The anti-neuroblastoma mechanism included inhibition of aurora kinase signalling as indicated by decreased phosphorylation of the aurora kinase substrate histone H3, cell cycle inhibition in G2/M phase, and induction of apoptosis. The activity of alisertib but not of tozasertib was affected by ABCB1 expression. Aurora kinase inhibitors induced a p53 response and their activity was enhanced in combination with the MDM2 inhibitor and p53 activator nutlin-3 in p53 wild-type cells. In conclusion, aurora kinases are potential drug targets in therapy-refractory neuroblastoma, in particular for the vast majority of p53 wild-type cases.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: PLoS ONE, Sept 30, 2014, Vol.9(9)
    Description: Aurora kinase inhibitors displayed activity in pre-clinical neuroblastoma models. Here, we studied the effects of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) and the aurora kinase inhibitor alisertib (MLN8237) that shows some specificity for aurora kinase A over aurora kinase B in a panel of neuroblastoma cell lines with acquired drug resistance. Both compounds displayed anti-neuroblastoma activity in the nanomolar range. The anti-neuroblastoma mechanism included inhibition of aurora kinase signalling as indicated by decreased phosphorylation of the aurora kinase substrate histone H3, cell cycle inhibition in G2/M phase, and induction of apoptosis. The activity of alisertib but not of tozasertib was affected by ABCB1 expression. Aurora kinase inhibitors induced a p53 response and their activity was enhanced in combination with the MDM2 inhibitor and p53 activator nutlin-3 in p53 wild-type cells. In conclusion, aurora kinases are potential drug targets in therapy-refractory neuroblastoma, in particular for the vast majority of p53 wild-type cases.
    Keywords: Tumor Proteins ; Apoptosis ; Phosphotransferases ; Neuroblastoma
    ISSN: 1932-6203
    Source: Cengage Learning, Inc.
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  • 4
    Language: English
    In: Biochemical Society transactions, August 2014, Vol.42(4), pp.752-7
    Description: Various experimental strategies aim to (re)activate p53 signalling in cancer cells. The most advanced clinically are small-molecule inhibitors of the autoregulatory interaction between p53 and MDM2 (murine double minute 2). Different MDM2 inhibitors are currently under investigation in clinical trials. As for other targeted anti-cancer therapy approaches, relatively rapid resistance acquisition may limit the clinical efficacy of MDM2 inhibitors. In particular, MDM2 inhibitors were shown to induce p53 mutations in experimental systems. In the present article, we summarize what is known about MDM2 inhibitors as anti-cancer drugs with a focus on the acquisition of resistance to these compounds.
    Keywords: Antineoplastic Agents -- Therapeutic Use ; Neoplasms -- Drug Therapy ; Proto-Oncogene Proteins C-Mdm2 -- Antagonists & Inhibitors
    ISSN: 03005127
    E-ISSN: 1470-8752
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  • 5
    In: BMC Research Notes, 2014, Vol.7, p.384-384
    Description: Background Different flavonoids are known to interfere with influenza A virus replication. Recently, we showed that the structurally similar flavonoids baicalein and biochanin A inhibit highly pathogenic avian H5N1 influenza A virus replication by different mechanisms in A549 lung cells. Here, we investigated the effects of both compounds on H5N1-induced reactive oxygen species (ROS) formation and the role of ROS formation during H5N1 replication. Findings Baicalein and biochanin A enhanced H5N1-induced ROS formation in A549 cells and primary human monocyte-derived macrophages. Suppression of ROS formation induced by baicalein and biochanin A using the antioxidant N-acetyl-L-cysteine strongly increased the anti-H5N1 activity of both compounds in A549 cells but not in macrophages. Conclusions These findings emphasise that flavonoids induce complex pharmacological actions some of which may interfere with H5N1 replication while others may support H5N1 replication. A more detailed understanding of these actions and the underlying structure-activity relationships is needed to design agents with optimised anti-H5N1 activity.
    Keywords: Short Report ; H5n1 ; Biochanin A ; Baicalein ; Antiviral ; Reactive Oxygen Species ; N-Acetyl-L-Cysteine
    E-ISSN: 1756-0500
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  • 6
    Language: English
    In: BMC research notes, 10 October 2014, Vol.7, pp.710
    Description: Various kinase inhibitors are known to be ATP-binding cassette (ABC) transporter substrates and resistance acquisition to kinase inhibitors has been associated to increased ABC transporter expression. Here, we investigated the role of the ABC transporters ABCB1, ABCC1, and ABCG2 during melanoma cell resistance acquisition to the V600-mutant BRAF inhibitors PLX4032 (vemurafenib) and PLX4720. PLX4032 had previously been shown to interfere with ABCB1 and ABCG2. PLX4720 had been demonstrated to interact with ABCB1 but to a lower extent than PLX4032. PLX4032 and PLX4720 affected ABCC1- and ABCG2-mediated drug transport in a similar fashion. In a panel of 16 V600E BRAF-mutated melanoma cell lines consisting of four parental cell lines and their sub-lines with acquired resistance to PLX4032, PLX4720, vincristine (cytotoxic ABCB1 and ABCC1 substrate), or mitoxantrone (cytotoxic ABCG2 substrate), we detected enhanced ABC transporter expression in 4/4 cytotoxic ABC transporter substrate-resistant, 3/4 PLX4720-resistant, and 1/4 PLX4032-resistant melanoma cell lines. PLX4032 has the potential to induce ABC transporter expression but this potential is lower than that of PLX4720 or cytotoxic ABC transporter substrates. Since ABC transporters confer multi-drug resistance, this is of relevance for the design of next-line therapies.
    Keywords: Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; ATP-Binding Cassette Transporters -- Drug Effects ; Antineoplastic Agents -- Pharmacology ; Indoles -- Pharmacology ; Protein Kinase Inhibitors -- Pharmacology ; Proto-Oncogene Proteins B-Raf -- Antagonists & Inhibitors ; Sulfonamides -- Pharmacology
    E-ISSN: 1756-0500
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  • 7
    Description: PURPOSE: The clinically approved oncogenic BRAF inhibitor PLX4032 (vemurafenib) was shown to be a substrate of the ATP-binding cassette (ABC) transporter ABCB1. Here, we compared PLX4032 and its structurally closely related precursor compound PLX4720 for their interference with ABCB1 and the ABCB1-mediated compound transport using docking and cell culture experiments.METHODS: For the docking study of PLX4032 and PLX4720 with ABCB1, we analysed binding of both compounds to mouse Abcb1a and to human ABCB1 using a homology model of human ABCB1 based on the 3D structure of Abcb1a. Naturally ABCB1 expressing cells including V600E BRAF-mutated and BRAF wild-type melanoma cells and cells transduced with a lentiviral vector encoding for ABCB1 were used as cell culture models. ABCB1 expression and function were studied by the use of fluorescent and cytotoxic ABCB1 substrates in combination with ABCB1 inhibitors.RESULTS: Docking experiments predicted PLX4032 to interact stronger with ABCB1 than PLX4720. Experimental studies using different cellular models and structurally different ABCB1 substrates confirmed that PLX4032 interfered stronger with ABCB1 function than PLX4720. For example, PLX4032 (20 µM) induced a 4-fold enhanced rhodamine 123 accumulation compared to PLX4720 (20 µM) in ABCB1-transduced UKF-NB-3 cells and reduced the IC₅₀ for the cytotoxic ABCB1 substrate vincristine in this model by 21-fold in contrast to a 9-fold decrease induced by PLX4720.CONCLUSIONS: PLX4032 exerted stronger effects on ABCB1-mediated drug transport than PLX4720. This indicates that small changes in a molecule can substantially modify its interaction with ABCB1, a promiscuous transporter that transports structurally different compounds.
    Keywords: Pharmacy, Therapeutics, & Pharmacology;
    ISSN: 14821826
    E-ISSN: 14821826
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  • 8
    Language: English
    In: International journal of clinical pharmacology and therapeutics, January 2014, Vol.52(1), pp.92-4
    Keywords: Epithelial-Mesenchymal Transition ; Carcinoma, Non-Small-Cell Lung -- Drug Therapy ; Erbb Receptors -- Antagonists & Inhibitors ; Lung Neoplasms -- Drug Therapy ; Micrornas -- Physiology
    ISSN: 0946-1965
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  • 9
    In: European Journal of Cardio-Thoracic Surgery, 2014, Vol. 46(5), pp.877-886
    Description: OBJECTIVES: According to the actual treatment strategies of lung cancer, the current therapeutic regimen is an individualized, multidisciplinary concept. The development of chemoresistance in the last decade represents the most important obstacle to an effective treatment. In our study, we examined a new therapeutic alternative in the treatment of multiresistant lung adenocarcinoma via siRNA-specific transfection of six crucial molecules involved in lung carcinogenesis [serum response factor(SFR), E2F1, Survivin, hypoxia inducible factor1 (HIF1), HIF2 and signal transducer and activator of transcription (STAT3)].METHODS: Three chemoresistant A549 adenocarcinoma cells were cultured under standard conditions at 37°C and 5% CO2. The chemoresistance against Vinflunine, Vinorelbine and Methotrexate was induced artificially. The A549 cells were transfected for 2 h at 37°C with specific siRNA targeting SRF, E2F1, Survivin, HIF1, HIF2 and STAT3 in a non-viral manner. The efficiency of siRNA silencing was evaluated via quantitative real-time polymerase chain reaction, whereas the surviving cells after siRNA transfection as predictor factor for tumoural growth were analysed with a CASY cell counter 3 days after transfection.RESULTS: The response of the chemotherapeutic resistant adenocarcinoma cells after siRNA transfection was concentration-dependent at both 25 and 100 nM. The CASY analysis showed a very effective suppression of adenocarcinoma cells in Vinorelbine, Vinflunine and Methotrexate groups, with significantly better results in comparison with the control group.CONCLUSIONS: In our study, we emphasized that siRNA interference might represent a productive platform for further research in order to investigate whether a new regimen in the treatment of multiresistant non-small-cell lung cancer could be established in vivo in the context of a multimodal cancer therapy.
    Keywords: Sirna ; Nsclc ; Target Molecules ; Chemoresistance ; Multimodality Concept
    ISSN: 1010-7940
    E-ISSN: 1873-734X
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  • 10
    In: Neuro-Oncology, 2014, Vol. 16(11), pp.1469-1477
    Description: BACKGROUND: Experimental findings have suggested that human cytomegalovirus (HCMV) infection of tumor cells may exert oncomodulatory effects that enhance tumor malignancy. However, controversial findings have been published on the presence of HCMV in malignant tumors. Here, we present the first study that systematically investigates HCMV infection in human nervous system tumors by highly sensitive immunohistochemistry in correlation with the HCMV serostatus of the patients.METHODS: Immunohistochemical and quantitative PCR-based methods to detect different HCMV antigens and genomic HCMV DNA were optimized prior to the investigation of pathological samples. Moreover, the pathological results were matched with the HCMV serostatus of the patients.RESULTS: HCMV immediate-early, late, and pp65 antigens could be detected in single cells from HCMV strain Hi91-infected UKF-NB-4 neuroblastoma cells after 1:1024 dilution with noninfected UKF-NB-4 cells. Genomic HCMV DNA could be detected in copy numbers as low as 430 copies/mL. However, we did not detect HCMV in tumors from a cohort of 123 glioblastoma, medulloblastoma, or neuroblastoma patients. Notably, we detected nonspecifically positive staining in tumor tissues of HCMV seropositive and seronegative glioblastoma patients. The HCMV serostatus of 67 glioblastoma patients matched the general epidemiological prevalence data for Western countries (72% of female and 57% of male glioblastoma patients were HCMV seropositive). Median survival was not significantly different in HCMV seropositive versus seronegative glioblastoma patients.CONCLUSIONS: The prevalence of HCMV-infected tumor cells may be much lower than previously reported based on highly sensitive detection methods.
    Keywords: Cytomegalovirus ; Glioma ; Oncomodulation
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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