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Berlin Brandenburg

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  • Wiese, Michael  (7)
  • Rothweiler, Florian  (7)
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  • 1
    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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  • 2
    Language: English
    In: BMC research notes, 28 September 2015, Vol.8, pp.484
    Description: Recently, we have shown that the ATP-binding cassette (ABC) transporter ABCB1 interferes with the anti-cancer activity of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) but not of the aurora kinase A and B inhibitor alisertib (MLN8237). Preliminary data had suggested tozasertib also to be a substrate of the ABC transporter ABCG2, another ABC transporter potentially involved in cancer cell drug resistance. Here, we studied the effect of ABCG2 on the activity of tozasertib and alisertib. The tozasertib concentration that reduces cell viability by 50% (IC50) was dramatically increased in ABCG2-transduced UKF-NB-3(ABCG2) cells (48.8-fold) compared to UKF-NB-3 cells and vector-transduced control cells. The ABCG2 inhibitor WK-X-34 reduced tozasertib IC50 to the level of non-ABCG2-expressing UKF-NB-3 cells. Furthermore, ABCG2 depletion from UKF-NB-3(ABCG2) cells using another lentiviral vector expressing an shRNA against the bicistronic mRNA of ABCG2 and eGFP largely re-sensitised these cells to tozasertib. In contrast, alisertib activity was not affected by ABCG2 expression. Tozasertib but not alisertib activity is affected by ABCG2 expression. This should be considered within the design and analysis of experiments and clinical trials investigating these compounds.
    Keywords: ATP-Binding Cassette Transporters -- Metabolism ; Aurora Kinases -- Antagonists & Inhibitors ; Azepines -- Pharmacology ; Neoplasm Proteins -- Metabolism ; Piperazines -- Pharmacology ; Protein Kinase Inhibitors -- Pharmacology ; Pyrimidines -- Pharmacology
    E-ISSN: 1756-0500
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  • 3
    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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  • 4
    Language: English
    In: Oncotarget, 08 March 2016, Vol.7(10), pp.11664-76
    Description: Pirinixic acid derivatives, a new class of drug candidates for a range of diseases, interfere with targets including PPARα, PPARγ, 5-lipoxygenase (5-LO), and microsomal prostaglandin and E2 synthase-1 (mPGES1). Since 5-LO, mPGES1, PPARα, and PPARγ represent potential anti-cancer drug targets, we here investigated the effects of 39 pirinixic acid derivatives on prostate cancer (PC-3) and neuroblastoma (UKF-NB-3) cell viability and, subsequently, the effects of selected compounds on drug-resistant neuroblastoma cells. Few compounds affected cancer cell viability in low micromolar concentrations but there was no correlation between the anti-cancer effects and the effects on 5-LO, mPGES1, PPARα, or PPARγ. Most strikingly, pirinixic acid derivatives interfered with drug transport by the ATP-binding cassette (ABC) transporter ABCB1 in a drug-specific fashion. LP117, the compound that exerted the strongest effect on ABCB1, interfered in the investigated concentrations of up to 2μM with the ABCB1-mediated transport of vincristine, vinorelbine, actinomycin D, paclitaxel, and calcein-AM but not of doxorubicin, rhodamine 123, or JC-1. In silico docking studies identified differences in the interaction profiles of the investigated ABCB1 substrates with the known ABCB1 binding sites that may explain the substrate-specific effects of LP117. Thus, pirinixic acid derivatives may offer potential as drug-specific modulators of ABCB1-mediated drug transport.
    Keywords: Abcb1 ; Cancer ; Drug Resistance ; Pirinixic Acid ; Pirinixic Acid Derivative ; Pyrimidines -- Pharmacology
    E-ISSN: 1949-2553
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  • 5
    Language: English
    In: Neoplasia, January 2009, Vol.11(1), pp.1-9
    Description: Although human cytomegalovirus (HCMV) is generally not regarded to be an oncogenic virus, HCMV infection has been implicated in malignant diseases from different cancer entities. On the basis of our experimental findings, we developed the concept of “oncomodulation” to better explain the role of HCMV in cancer. Oncomodulation means that HCMV infects tumor cells and increases their malignancy. By this concept, HCMV was proposed to be a therapeutic target in a fraction of cancer patients. However, the clinical relevance of HCMV-induced oncomodulation remains to be clarified. One central question that has to be definitively answered is if HCMV establishes persistent virus replication in tumor cells or not. In our eyes, recent clinical findings from different groups in glioblastoma patients and especially the detection of a correlation between the numbers of HCMV-infected glioblastoma cells and tumor stage (malignancy) strongly increase the evidence that HCMV may exert oncomodulatory effects. Here, we summarize the currently available knowledge about the molecular mechanisms that may contribute to oncomodulation by HCMV as well as the clinical findings that suggest that a fraction of tumors from different entities is indeed infected with HCMV.
    Keywords: Medicine
    ISSN: 1476-5586
    ISSN: 20452322
    E-ISSN: 1476-5586
    E-ISSN: 20452322
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  • 6
    Language: English
    In: Neoplasia, December 2010, Vol.12(12), pp.1023,IN10-1030,IN17
    Description: The human immunodeficiency virus (HIV) protease inhibitor saquinavir shows anticancer activity. Although its nitric oxide-modified derivative saquinavir-NO (saq-NO) was less toxic to normal cells, it exerted stronger inhibition of B16 melanoma growth in syngeneic C57BL/6 mice than saquinavir did. Saq-NO has been shown to block proliferation, upregulate p53 expression, and promote differentiation of C6 glioma and B16 cells. The anticancer activity of substances is frequently hampered by cancer cell chemoresistance mechanisms. Therefore, we here investigated the roles of p53 and the ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein 1 (BCRP1) in cancer cell sensitivity to saq-NO to get more information about the potential of saq-NO as anticancer drug. Saq-NO exerted anticancer effects in lower concentrations than saquinavir in a panel of human cancer cell lines. Neither p53 mutation or depletion nor expression of P-gp, MRP1, or BCRP1 affected anticancer activity of saq-NO or saquinavir. Moreover, saq-NO sensitized P-gp-, MRP1-, or BCRP1-expressing cancer cells to chemotherapy. Saq-NO induced enhanced sensitization of P-gp- or MRP1-expressing cancer cells to chemotherapy compared with saquinavir, whereas both substances similarly sensitized BCRP1-expressing cells. Washout kinetics and ABC transporter ATPase activities demonstrated that saq-NO is a substrate of P-gp as well as of MRP1. These data support the further investigation of saq-NO as an anticancer drug, especially in multidrug-resistant tumors.
    Keywords: Medicine
    ISSN: 1476-5586
    E-ISSN: 1476-5586
    Source: ScienceDirect Journals (Elsevier)
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  • 7
    Language: English
    In: Neoplasia (New York, N.Y.), December 2010, Vol.12(12), pp.1023-30
    Description: The human immunodeficiency virus (HIV) protease inhibitor saquinavir shows anticancer activity. Although its nitric oxide-modified derivative saquinavir-NO (saq-NO) was less toxic to normal cells, it exerted stronger inhibition of B16 melanoma growth in syngeneic C57BL/6 mice than saquinavir did. Saq-NO has been shown to block proliferation, upregulate p53 expression, and promote differentiation of C6 glioma and B16 cells. The anticancer activity of substances is frequently hampered by cancer cell chemoresistance mechanisms. Therefore, we here investigated the roles of p53 and the ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein 1 (BCRP1) in cancer cell sensitivity to saq-NO to get more information about the potential of saq-NO as anticancer drug. Saq-NO exerted anticancer effects in lower concentrations than saquinavir in a panel of human cancer cell lines. Neither p53 mutation or depletion nor expression of P-gp, MRP1, or BCRP1 affected anticancer activity of saq-NO or saquinavir. Moreover, saq-NO sensitized P-gp-, MRP1-, or BCRP1-expressing cancer cells to chemotherapy. Saq-NO induced enhanced sensitization of P-gp- or MRP1-expressing cancer cells to chemotherapy compared with saquinavir, whereas both substances similarly sensitized BCRP1-expressing cells. Washout kinetics and ABC transporter ATPase activities demonstrated that saq-NO is a substrate of P-gp as well as of MRP1. These data support the further investigation of saq-NO as an anticancer drug, especially in multidrug-resistant tumors.
    Keywords: Drug Resistance, Neoplasm ; ATP-Binding Cassette Transporters -- Metabolism ; Antineoplastic Agents -- Pharmacology ; Cell Proliferation -- Drug Effects ; Saquinavir -- Analogs & Derivatives
    E-ISSN: 1476-5586
    Source: MEDLINE/PubMed (U.S. National Library of Medicine)
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