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Berlin Brandenburg

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  • Rothweiler, Florian  (10)
  • Michaelis, M.  (10)
  • Cancer
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  • 1
    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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  • 2
    Language: English
    In: Biomaterials, 2010, Vol.31(8), pp.2388-2398
    Description: Specific transport of anti-cancer drugs into tumor cells may result in increased therapeutic efficacy and decreased adverse events. Expression of αvβ3 integrin is enhanced in various types of cancer and monoclonal antibodies (mAbs) directed against αvβ3 integrins hold promise for anti-cancer therapy. DI17E6 is a monoclonal antibody directed against αv integrins that inhibits growth of melanomas and and inhibits angiogenesis due to interference with αvβ3 integrins. Here, DI17E6 was covalently coupled to human serum albumin nanoparticles. Resulting nanoparticles specifically targeted αvβ3 integrin positive melanoma cells. Moreover, doxorubicin loaded DI17E6 nanoparticles showed increased cytotoxic activity in αvβ3-positive melanoma cells than the free drug. Therefore, DI17E6-coupled human serum albumin nanoparticles represent a potential delivery system for targeted drug transport into αvβ3-positive cells.
    Keywords: Albumin ; Chemotherapy ; Drug Delivery ; Ecm (Extracellular Matrix) ; Integrin ; Nanoparticles ; Medicine ; Engineering
    ISSN: 0142-9612
    E-ISSN: 1878-5905
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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, 06 September 2016, Vol.7(36), pp.58051-58064
    Description: The CDK inhibitor SNS-032 had previously exerted promising anti-neuroblastoma activity via CDK7 and 9 inhibition. ABCB1 expression was identified as major determinant of SNS-032 resistance. Here, we investigated the role of ABCB1 in acquired SNS-032 resistance. In contrast to ABCB1-expressing UKF-NB-3 sub-lines resistant to other ABCB1 substrates, SNS-032-adapted UKF-NB-3 (UKF-NB-3rSNS- 032300nM) cells remained sensitive to the non-ABCB1 substrate cisplatin and were completely re-sensitized to cytotoxic ABCB1 substrates by ABCB1 inhibition. Moreover, UKF-NB-3rSNS-032300nM cells remained similarly sensitive to CDK7 and 9 inhibition as UKF-NB-3 cells. In contrast, SHEPrSNS-0322000nM, the SNS-032-resistant sub-line of the neuroblastoma cell line SHEP, displayed low level SNS-032 resistance also when ABCB1 was inhibited. This discrepancy may be explained by the higher SNS-032 concentrations that were used to establish SHEPrSNS-0322000nM cells, since SHEP cells intrinsically express ABCB1 and are less sensitive to SNS-032 (IC50 912 nM) than UKF-NB-3 cells (IC50 153 nM). In conclusion, we show that ABCB1 expression represents the primary (sometimes exclusive) resistance mechanism in neuroblastoma cells with acquired resistance to SNS-032. Thus, ABCB1 inhibitors may increase the SNS-032 efficacy in ABCB1-expressing cells and prolong or avoid resistance formation.
    Keywords: Abcb1 ; Cdk Inhibitor ; Cancer ; Multi-Drug Resistance ; Neuroblastoma ; Drug Resistance, Neoplasm ; Antineoplastic Agents -- Pharmacology ; Neuroblastoma -- Drug Therapy ; Oxazoles -- Pharmacology ; Protein Kinase Inhibitors -- Pharmacology ; Thiazoles -- Pharmacology
    E-ISSN: 1949-2553
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  • 5
    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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  • 6
    Language: English
    In: Cell death & disease, 13 October 2016, Vol.7(10), pp.e2410
    Description: Resistance formation after initial therapy response (acquired resistance) is common in high-risk neuroblastoma patients. YM155 is a drug candidate that was introduced as a survivin suppressant. This mechanism was later challenged, and DNA damage induction and Mcl-1 depletion were suggested instead. Here we investigated the efficacy and mechanism of action of YM155 in neuroblastoma cells with acquired drug resistance. The efficacy of YM155 was determined in neuroblastoma cell lines and their sublines with acquired resistance to clinically relevant drugs. Survivin levels, Mcl-1 levels, and DNA damage formation were determined in response to YM155. RNAi-mediated depletion of survivin, Mcl-1, and p53 was performed to investigate their roles during YM155 treatment. Clinical YM155 concentrations affected the viability of drug-resistant neuroblastoma cells through survivin depletion and p53 activation. MDM2 inhibitor-induced p53 activation further enhanced YM155 activity. Loss of p53 function generally affected anti-neuroblastoma approaches targeting survivin. Upregulation of ABCB1 (causes YM155 efflux) and downregulation of SLC35F2 (causes YM155 uptake) mediated YM155-specific resistance. YM155-adapted cells displayed increased ABCB1 levels, decreased SLC35F2 levels, and a p53 mutation. YM155-adapted neuroblastoma cells were also characterized by decreased sensitivity to RNAi-mediated survivin depletion, further confirming survivin as a critical YM155 target in neuroblastoma. In conclusion, YM155 targets survivin in neuroblastoma. Furthermore, survivin is a promising therapeutic target for p53 wild-type neuroblastomas after resistance acquisition (neuroblastomas are rarely p53-mutated), potentially in combination with p53 activators. In addition, we show that the adaptation of cancer cells to molecular-targeted anticancer drugs is an effective strategy to elucidate a drug's mechanism of action.
    Keywords: Drug Resistance, Neoplasm -- Drug Effects ; Imidazoles -- Pharmacology ; Inhibitor of Apoptosis Proteins -- Metabolism ; Naphthoquinones -- Pharmacology ; Neuroblastoma -- Metabolism
    E-ISSN: 2041-4889
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  • 7
    Language: English
    In: PLoS ONE, 01 January 2017, Vol.12(2), p.e0172140
    Description: The formation of acquired drug resistance is a major reason for the failure of anti-cancer therapies after initial response. Here, we introduce a novel model of acquired oxaliplatin resistance, a sub-line of the non-MYCN-amplified neuroblastoma cell line SK-N-AS that was adapted to growth in the presence of 4000 ng/mL oxaliplatin (SK-N-ASrOXALI4000). SK-N-ASrOXALI4000 cells displayed enhanced chromosomal aberrations compared to SK-N-AS, as indicated by 24-chromosome fluorescence in situ hybridisation. Moreover, SK-N-ASrOXALI4000 cells were resistant not only to oxaliplatin but also to the two other commonly used anti-cancer platinum agents cisplatin and carboplatin. SK-N-ASrOXALI4000 cells exhibited a stable resistance phenotype that was not affected by culturing the cells for 10 weeks in the absence of oxaliplatin. Interestingly, SK-N-ASrOXALI4000 cells showed no cross resistance to gemcitabine and increased sensitivity to doxorubicin and UVC radiation, alternative treatments that like platinum drugs target DNA integrity. Notably, UVC-induced DNA damage is thought to be predominantly repaired by nucleotide excision repair and nucleotide excision repair has been described as the main oxaliplatin-induced DNA damage repair system. SK-N-ASrOXALI4000 cells were also more sensitive to lysis by influenza A virus, a candidate for oncolytic therapy, than SK-N-AS cells. In conclusion, we introduce a novel oxaliplatin resistance model. The oxaliplatin resistance mechanisms in SK-N-ASrOXALI4000 cells appear to be complex and not to directly depend on enhanced DNA repair capacity. Models of oxaliplatin resistance are of particular relevance since research on platinum drugs has so far predominantly focused on cisplatin and carboplatin.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 8
    Language: English
    In: Biochemical Pharmacology, 15 January 2010, Vol.79(2), pp.130-136
    Description: Artemisinin derivatives are well-tolerated anti-malaria drugs that also exert anti-cancer activity. Here, we investigated artemisinin and its derivatives dihydroartemisinin and artesunate in a panel of chemosensitive and chemoresistant human neuroblastoma cells as well as in primary neuroblastoma cultures. Only dihydroartemisinin and artesunate affected neuroblastoma cell viability with artesunate being more active. Artesunate-induced apoptosis and reactive oxygen species in neuroblastoma cells. Of 16 cell lines and two primary cultures, only UKF-NB-3 CDDP showed low sensitivity to artesunate. Characteristic gene expression signatures based on a previous analysis of artesunate resistance in the NCI60 cell line panel clearly separated UKF-NB-3 CDDP from the other cell lines. -Buthionine-S,R-sulfoximine, an inhibitor of GCL (glutamate–cysteine ligase), resensitised in part UKF-NB-3 CDDP cells to artesunate. This finding together with bioinformatic analysis of expression of genes involved in glutathione metabolism showed that this pathway is involved in artesunate resistance. These data indicate that neuroblastoma represents an artesunate-sensitive cancer entity and that artesunate is also effective in chemoresistant neuroblastoma cells.
    Keywords: Neuroblastoma ; Artesunate ; Artemisinin ; Chemoresistance ; Cancer ; Chemotherapy ; Pharmacy, Therapeutics, & Pharmacology ; Chemistry
    ISSN: 0006-2952
    E-ISSN: 1873-2968
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  • 9
    Language: English
    In: Cancer Letters, 2007, Vol.250(1), pp.107-116
    Description: The efficacy of Onconase on the growth of a panel of chemosensitive and chemoresistant neuroblastoma cell lines was investigated. Onconase decreased cell viability of chemosensitive (IMR-32, UKF-NB-3) and chemoresistant neuroblastoma cell lines characterised by high expression of P-glycoprotein (P-gp) (UKF-NB-3 DOX ) or by high P-gp expression in combination with mutated p53 (UKF-NB-3 VCR , Be(2)-C), in a similar manner. Moreover, Onconase caused cell cycle block in G1 phase and induced caspase-independent cell death. Transmission electron microscope investigations suggested that Onconase-induced autophagy contributes to Onconase-induced cell death. Antitumour activity of Onconase against naïve and drug-resistant neuroblastoma xenografts was confirmed in animals.
    Keywords: Onconase ; Neuroblastoma ; Multi-Drug-Resistance ; P-Glycoprotein ; P53 ; Medicine
    ISSN: 0304-3835
    E-ISSN: 1872-7980
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  • 10
    Language: English
    In: International Journal of Oncology, February 2006, Vol.28(2), pp.439-446
    Description: The proteasome inhibitor bortezomib (Velcade®) was recently approved for the treatment of therapy-refractive multiple myeloma and is under investigation for numerous other types of cancer. A phase I clinical trial in paediatric patients resulted in tolerable toxicity. Since the emergence of chemoresistance represents one of the major drawbacks in cancer therapy, we investigated the influence of bortezomib on multi-drug resistant human neuroblastoma cell lines characterised by P-glycoprotein expression and p53 mutation. Nanomolar concentrations of bortezomib inhibited the cell cycle and induced apoptosis in chemosensitive as well as in chemoresistant cell lines. in vivo growth of chemosensitive and chemoresistant neuroblastoma cell lines was inhibited to a similar extent. In addition, bortezomib inhibited vessel formation in neuroblastoma xenografts. These findings and the favourable toxicity profile of bortezomib in children make it reasonable to further pursue additional development of the drug for the treatment of neuroblastoma and other paediatric solid tumours.
    ISSN: 1019-6439
    Source: Spandidios Publications (Spandidos Publications Ltd.)
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