Arjan W Griffioen

VU University Medical Center, Amsterdamo, North Holland, Netherlands

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Publications (197)994.53 Total impact

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    ABSTRACT: Calixarene 0118 is a potent anti-angiogenic agent that effectively inhibited tumor growth in preclinical studies, and is currently being evaluated in a phase I clinical trial. We have designed two close mimetics of calixarene 0118 containing a terminal alkynyl-functional group, and developed an optimized semi-automated procedure for radiolabeling with 2-[(18)F]fluoroethylazide using click chemistry. Following semi-preparative HPLC purification and formulation, the lower-rim modified analog [(18)F]6 and the equatorially labeled [(18)F]13 were obtained in >97% radiochemical purity and overall decay-corrected isolated radiochemical yields of 18.7 ± 2.7% (n = 4) and 10.2 ± 5.0% (n = 4), respectively, in a total synthesis time of about 2 h. Preliminary in vivo studies in nude mice bearing human tumor xenografts revealed highest accumulation of both tracers in the liver, followed by spleen, kidney, lung and bone, with no substantial uptake in the tumor. Still, these first-in-class radiotracers are a valuable tool for pharmacokinetic profiling and improvement of calixarene-based anti-angiogenic therapeutics in the future, as similar radiolabeling strategies may be applied to other compounds in the calixarene series. The cold reference compounds of the radiotracers were characterized in terms of cytotoxicity and anti-proliferative effects on HUVEC cells and on MA148 human ovarian carcinoma cells, along with the respective precursors, a small series of 0118 analogs modified with short-chain linear alkyl substituents, and a PEG3-spaced calixarene dimer. While all of the new analogs proved at least equipotent to parent 0118, some of them inhibited HUVEC and MA148 cell growth almost 4- and 10-fold more effectively, rendering these analogs promising candidates for further evaluation in anti-angiogenic cancer therapy. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
    European Journal of Medicinal Chemistry. 01/2015; 89:279–295.
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    ABSTRACT: The growth of new blood vessels is a key event in many (patho)physiological processes, including embryogenesis, wound healing, inflammatory diseases, and cancer. Neovascularization requires different, well-coordinated actions of endothelial cells, i.e., the cells lining the luminal side of all blood vessels. Galectins are involved in several of these activities. In this chapter we describe methods to study galectins and galectin inhibition in three key functions of endothelial cells during angiogenesis, i.e., endothelial cell migration, endothelial cell sprouting, and endothelial cell network formation.
    Methods in molecular biology (Clifton, N.J.) 01/2015; 1207:285-91. · 1.29 Impact Factor
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    ABSTRACT: Angiogenesis is a complex multi-process involving various activities of endothelial cells. These activities are influenced in vivo by environmental conditions like interactions with other cell types and the microenvironment. Galectins play a role in several of these interactions and are therefore required for proper execution of in vivo angiogenesis. In this chapter we describe a method to study galectins and galectin inhibitors during physiologic and pathophysiologic angiogenesis in vivo using the chicken chorioallantoic membrane (CAM) assay.
    Methods in molecular biology (Clifton, N.J.) 01/2015; 1207:305-15. · 1.29 Impact Factor
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    ABSTRACT: The cell is a complex system involving numerous components, which may often interact in a non-linear dynamic manner. Diseases at the cellular level are thus likely to involve multiple cellular constituents and pathways. As some drugs, or drug combinations, may act synergistically on these multiple pathways, they might be more effective than the respective single target agents. Optimizing a drug mixture for a given disease in a particular patient is particularly challenging due to both the difficulty in the selection of the drug mixture components to start out with, and the all-important doses of these drugs to be applied. For n concentrations of m drugs, in principle, n(m) combinations will have to be tested. As this may lead to a costly and time-consuming investigation for each individual patient, we have developed a Feedback System Control (FSC) technique which can rapidly select the optimal drug-dose combination from the often millions of possible combinations. By testing this FSC technique in a number of experimental systems representing different disease states, we found that the response of cells to multiple drugs is well described by a low order, rather smooth, drug-mixture-input/drug-effect-output multidimensional surface. The main consequences of this are that optimal drug combinations can be found in a surprisingly small number of tests, and that translation from in vitro to in vivo is simplified. This points to the possibility of personalized optimal drug mixtures in the near future. This unexpectedly simple input-output relationship may also lead to a simple solution for handling the issue of human diversity in cancer therapeutics.
    Physical Biology 11/2014; 11(6):065003. · 2.62 Impact Factor
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    ABSTRACT: Angiostatic therapies are now routinely embedded in the daily clinical management of cancer. Although these agents clearly benefit patient survival rates, the effect is only moderate with sometimes considerable side effects. A major cause of failure in this respect is the induction of resistance and tolerability against these drugs. Most angiostatic drugs are tyrosine kinase inhibitors that aim to inhibit or neutralize the activity of tumour-produced growth factors. Frustrating the tumour cells in this way results in genetic adaptations in the cells, turning them into mutants that are dependent on other growth mechanisms. It may therefore be necessary to shift to another class of drugs that directly target the tumour vasculature. It is evident that improvement of future angiogenesis inhibitors can only arise from two efforts. First, through the identification of better targets, preferably specifically expressed in the tumour vasculature. Secondly, through the development of combination therapies. The present review highlights the current efforts and challenges in trying to develop effective angiostatic combination therapies.
    Biochemical Society Transactions 11/2014; 42(6):1608-1615. · 2.59 Impact Factor
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    Arjan W Griffioen, Victor L Thijssen
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    ABSTRACT: The expansion of solid tumors depends on the continuous ingrowth of new blood vessels out of pre-existing capillaries. Consequently, tumor neovascularization or tumor angiogenesis is considered a hallmark of cancer and an attractive target for cancer therapy. Tumor angiogenesis is mainly carried out by endothelial cells (EC), i.e., the cells lining the luminal vessel wall. These cells have to take on different functional activities in order to successfully make new tumor blood vessels. In the last decade it has become apparent that galectins are important regulators of tumor angiogenesis. In the present review we summarize the current knowledge regarding the role galectins in tumor angiogenesis focussing on the endothelial galectins, i.e., gal-1/-3/-8/-9.
    Annals of Translational Medicine. 09/2014; 2(9).
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    ABSTRACT: Based on the clinical success of platinum-based anti-cancer drugs such as cisplatin, carboplatin and oxaliplatin, a variety of other metal-based anti-cancer compounds are being investigated. In particular, a number of ruthenium-based compounds have been identified which exhibit unique biochemical properties and reduced toxicity profiles compared to the clinically used platinum-based drugs. We have developed a series of organometallic ruthenium(II)-arene complexes that were shown to exert anti-metastatic activity with relatively minor activity on primary tumor growth. Here, we show that the prototype compound, [Ru(η6-p-cymene)Cl2(pta)], where pta = 1,3,5-triaza-7-phosphaadamantane (RAPTA-C), reduces the growth of primary tumors in preclinical models for ovarian and colorectal carcinomas. When administered daily at relatively low doses (0.2 mg kg−1), RAPTA-C was shown to significantly reduce the growth of the A2780 ovarian carcinoma transplanted onto the chicken chorioallantoic membrane model. Similar activity was observed in LS174T colorectal carcinoma in athymic mice, albeit at a higher dose. In both models, a clear inhibition of microvessel density was observed, confirming the previously discovered anti-angiogenic mechanism of RAPTA-C. Biodistribution studies with radiolabeled (103Ru) RAPTA-C indicate that the compound is rapidly cleared from the organs and the bloodstream through excretion by the kidneys. As such, RAPTA-C is a promising compound for translation to clinical evaluation.
    Chemical Science 08/2014; DOI: 10.1039/c4sc01255k. · 8.31 Impact Factor
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    ABSTRACT: Metallothioneins (MTs) are small cysteine-rich proteins which are involved in e.g. metal homeostasis, metal detoxification and protection against oxidative stress. In addition, several MTs have been shown to regulate expression of proangiogenic growth factors like vascular endothelial growth factor. Detailed information about the expression and regulation of specific MT isoforms in endothelial cells (EC) is limited. We therefore performed extensive mRNA expression profiling of all known human MTs in EC. We found that the basal endothelial expression is restricted to MT1E, MT1X, MT2A, and MT3. Physiological activation of EC by exposure to serum increased the expression of MT1E and MT2A and induced the expression of MT1M. Furthermore, exposure to zinc or copper induced the expression of most MT1 isoforms, while hypoxia specifically increased the expression of MT1E, MT1M, MT1X, and MT3. Finally, knockdown of the dominant MT isoform in EC, i.e. MT2A, resulted in decreased proliferation and sprouting as well as in increased migration of human umbilical vein EC. Together, these findings provide a link between MTs and angiogenesis. © 2014 S. Karger AG, Basel.
    Journal of Vascular Research 08/2014; 51(3):231-238. · 2.43 Impact Factor
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    ABSTRACT: Tumor-angiogenesis is the multi-factorial process of sprouting of endothelial cells (EC) into micro-vessels to provide tumor cells with nutrients and oxygen. To explore miRNAs as therapeutic angiogenesis-inhibitors, we performed a functional screen to identify miRNAs that are able to decrease EC viability. We identified miRNA-7 (miR-7) as a potent negative regulator of angiogenesis. Introduction of miR-7 in EC resulted in strongly reduced cell viability, tube formation, sprouting and migration. Application of miR-7 in the chick chorioallantoic membrane assay led to a profound reduction of vascularization, similar to anti-angiogenic drug sunitinib. Local administration of miR-7 in an in vivo murine neuroblastoma tumor model significantly inhibited angiogenesis and tumor growth. Finally, systemic administration of miR-7 using a novel integrin-targeted biodegradable polymeric nanoparticles that targets both EC and tumor cells, strongly reduced angiogenesis and tumor proliferation in mice with human glioblastoma xenografts. Transcriptome analysis of miR-7 transfected EC in combination with in silico target prediction resulted in the identification of OGT as novel target gene of miR-7. Our study provides a comprehensive validation of miR-7 as novel anti-angiogenic therapeutic miRNA that can be systemically delivered to both EC and tumor cells and offers promise for miR-7 as novel anti-tumor therapeutic.
    Oncotarget 07/2014; · 6.64 Impact Factor
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    ABSTRACT: Angiogenesis is one of the hallmarks of cancer which renders it an attractive target for therapy of malignancies. Tumor growth suppression can be achieved by inhibiting angiogenesis since it would deprive tumor cells of oxygen and vital nutrients. Activation of endothelial cells of tumor vasculature is the first step in angiogenesis which is mediated by various factors. One of the major triggers in this process is vascular endothelial growth factor (VEGF) which binds to VEGF receptors on endothelial cells of tumor vessels. This induces a series of signaling cascades leading to activation of cellular processes involved in angiogenesis, and therefore down-regulation of VEGF receptor-2 (VEGFR-2) expression seems a viable option to inhibit angiogenesis. In our investigations, this aim has been pursued by using siRNA interfering with the expression of VEGFR-2. Since the discovery of RNA interference (RNAi) as a gene regulation process, successful delivery of small non-coding RNA has presented itself as a major challenge. In the current study, we have characterized a galectin-1 targeted anginex-coupled lipoplex (Angiplex) containing siRNA against the gene of VEGFR-2 as an angiostatic therapeutic. Angiplex particles had a size of approximately 120nm with a net negative charge and were stable in vitro. These particles were internalized in a specific manner by HUVECs compared to a non-targeted lipoplex system, and their uptake was higher than Lipofectamine 2000. Gene silencing efficiency of Angiplex was shown to be 61%.
    International Journal of Pharmaceutics 06/2014; · 3.99 Impact Factor
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    ABSTRACT: The N-terminal fragment of prolactin (16K PRL) inhibits tumor growth by impairing angiogenesis, but the underlying mechanisms are unknown. Here, we found that 16K PRL binds the fibrinolytic inhibitor plasminogen activator inhibitor-1 (PAI-1), which is known to contextually promote tumor angiogenesis and growth. Loss of PAI-1 abrogated the antitumoral and antiangiogenic effects of 16K PRL. PAI-1 bound the ternary complex PAI-1-urokinase-type plasminogen activator (uPA)-uPA receptor (uPAR), thereby exerting antiangiogenic effects. By inhibiting the antifibrinolytic activity of PAI-1, 16K PRL also protected mice against thromboembolism and promoted arterial clot lysis. Thus, by signaling through the PAI-1-uPA-uPAR complex, 16K PRL impairs tumor vascularization and growth and, by inhibiting the antifibrinolytic activity of PAI-1, promotes thrombolysis.
    Nature medicine. 06/2014;
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    Victor L Thijssen, Arjan W Griffioen
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    ABSTRACT: The growth of new blood vessels out of the pre-existing vasculature, i.e. angiogenesis, is executed by endothelial cells that normally form the inner lining of blood vessels. During angiogenesis these cells exert different activities which require interactions with other cells and with the extracellular environment. It has become evident that this frequently involves galectins since the members of this protein family facilitate interactions betweens cells and/or glycoproteins via carbohydrate-binding. In addition, they can regulate intracellular processes like signaling and splicing via non-carbohydrate interactions. We have previously reported on the role of galectin-1 and galectin-9 in endothelial cell function. Here we review the current knowledge of these two galectins in endothelial cell biology and angiogenesis. In addition, we describe the contribution of both galectins to other processes that involve the endothelium, including inflammation and coagulation. Finally, we discuss the challenges for future research in order to better understand how this 'sweet' couple exerts its multifunctional activities within the vasculature.
    Glycobiology 05/2014; · 3.54 Impact Factor
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    ABSTRACT: A ruthenium(II)-arene complex with a perfluoroalkyl-ligand was found to display remarkable selectivity towards cancer cells. IC50 values on several cancer cell lines are in the range of 25-45 μM and no cytotoxic effect was observed on non-tumorigenic (HEK-293) cells at concentrations up to 500 μM (the maximum concentration tested). Consequently, this complex was used as the basis for the development of a number of related derivatives, which were screened in cancerous and non-cancerous cell lines. The lead compound was then evaluated in vivo for anti-angiogenic activity in the CAM model and in a xenografted ovarian carcinoma tumor (A2780) grown on the CAM. A 90% reduction in the tumor growth was observed.
    Journal of Medicinal Chemistry 03/2014; · 5.61 Impact Factor
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    ABSTRACT: Photodynamic therapy (PDT) is an effective clinical treatment for a number of different cancers. PDT can induce hypoxia and inflammation, pro-angiogenic side effects, which may counteract its angio-occlusive mechanism. The combination of PDT with anti-angiogenic drugs offers a possibility for improved anti-tumour outcome. We used two tumour models to test the effects of the clinically approved angiostatic tyrosine kinase inhibitors sunitinib, sorafenib and axitinib in combination with PDT, and compared these results with the effects of bevacizumab, the anti-VEGF antibody, for the improvement of PDT. Best results were obtained from the combination of PDT and low-dose axitinib or sorafenib. Molecular analysis by PCR revealed that PDT in combination with axitinib suppressed VEGFR-2 expression in tumour vasculature. Treatment with bevacizumab, although effective as monotherapy, did not improve PDT outcome. In order to test for tumour vessel normalization effects, axitinib was also applied prior to PDT. The absence of improved PDT outcome in these experiments, as well as the lack of increased oxygenation in axitinib-treated tumours, suggests that vascular normalization did not occur. The current data imply that there is a future for certain anti-angiogenic agents to further improve the efficacy of photodynamic anti-cancer therapy.
    Journal of Cellular and Molecular Medicine 01/2014; · 4.75 Impact Factor
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    ABSTRACT: Approximately 30-40% of the patients with early stage non-small cell lung cancer (NSCLC) will present with recurrent disease within two years of resection. Here, we performed extensive galectin expression profiling in a retrospective study using frozen and paraffin embedded tumor tissues from 87 stage I/II NSCLC patients. Our data show that galectin mRNA expression in NSCLC is confined to galectin-1, -3, -4, -7, -8, and -9. Next to stage, univariable Cox regression analysis identified galectin-1, galectin-9FL and galectin-9Δ5 as possible prognostic markers. Kaplan-Meier survival estimates revealed that overall survival was significantly shorter in patients that express galectin-1 above median levels, i.e., 23.0 (2.9-43.1) vs. 59.9 (47.7-72.1) months (p = 0.020) as well as in patients that express galectin-9Δ5 or galectin-9FL below the median, resp. 59.9 (41.9-75.9) vs. 32.8 (8.7-56.9) months (p = 0.014) or 23.2 (-0.4-46.8) vs. 58.9 (42.9-74.9) months (p = 0.042). All three galectins were also prognostic for disease free survival. Multivariable Cox regression analysis showed that for OS, the most significant prognostic model included stage, age, gal-1 and gal-9Δ5 while the model for DFS included stage, age and gal-9Δ5. In conclusion, the current study confirms the prognostic value of galectin-1 and identifies galectin-9Δ5 as novel potential prognostic markers in early stage NSCLC. These findings could help to identify early stage NSCLC patients that might benefit most from adjuvant chemotherapy.
    PLoS ONE 01/2014; 9(9):e107988. · 3.53 Impact Factor
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    ABSTRACT: Galectins are carbohydrate binding proteins with versatile functions in tumor progression. Galectin-9, encoded by LGALS9, has been associated with metastasis and immunosuppresion. We previously reported on regulation of LGALS9 expression during endothelial cell activation. Here, we show increased galectin-9 protein levels in the endothelium of different tumors, including carcinomas of lung, liver, breast and kidney. Endothelial cells were found to express five LGALS9 splice variants, two of which have not been reported before. Splicing was found to be confined to exons 5, 6 and 10. Transfection of human microvascular endothelial cells (HMEC) with galectin-9∆5, a specific LGALS9 splice variant, induced a small but significant increase of proliferation, while migration was not affected by any LGALS9 splice variant. Application of recombinant galectin-9∆5 protein dose-dependently reduced proliferation and migration of HMEC as well as human umbilical vein endothelial cells in vitro. Enhanced sprouting and migration of HUVEC towards a galectin-9∆5 gradient was observed. Interestingly, galectin-9∆5 was found to induce a small inhibitory effect on angiogenesis in vivo. Collectively, these data show that endothelial cells regulate the expression and splicing of LGALS9 during angiogenesis. The function of the dominant splice variant, i.e. galectin-9∆5, in endothelial cell biology depends on the concentration and environmental context in which it is presented to the cells.
    Biochimica et Biophysica Acta 12/2013; · 4.66 Impact Factor
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    Current Angiogenesis. 12/2013; 2:157-161.
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    J Anal Bioanal Tech. 10/2013;
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    ABSTRACT: Heparan sulfate (HS), a long linear polysaccharide, is implicated in various steps of tumorigenesis, including angiogenesis. We successfully interfered with HS biosynthesis using a peracetylated 4-deoxy analog of the HS constituent GlcNAc and studied the compound's metabolic fate and its effect on angiogenesis. The 4-deoxy analog was activated intracellularly into UDP-4-deoxy-GlcNAc and HS expression was inhibited up to ~96% (IC50 = 16 µM). HS chain size was reduced, without detectable incorporation of the 4-deoxy analog, likely due to reduced levels of UDP-GlcNAc. Comprehensive gene expression analysis revealed reduced expression of genes regulated by HS binding growth factors as FGF-2 and VEGF. Cellular binding and signaling of these angiogenic factors was inhibited. Micro-injection in zebrafish embryos strongly reduced HS biosynthesis, and angiogenesis was inhibited in both zebrafish and chicken model systems. All these data identify 4-deoxy-GlcNAc as a potent inhibitor of HS synthesis which hampers pro-angiogenic signaling and neo-vessel formation.
    ACS Chemical Biology 08/2013; · 5.44 Impact Factor

Publication Stats

6k Citations
994.53 Total Impact Points

Institutions

  • 2009–2014
    • VU University Medical Center
      • • Department of Radiation Oncology
      • • Department of Radiotherapy
      Amsterdamo, North Holland, Netherlands
    • VU University Amsterdam
      • Department of Medical Oncology
      Amsterdam, North Holland, Netherlands
  • 2012
    • Netherlands Cancer Institute
      • Department of Urology
      Amsterdamo, North Holland, Netherlands
  • 2010–2012
    • École Polytechnique Fédérale de Lausanne
      • Institut interfacultaire de Bioingénierie
      Lausanne, VD, Switzerland
    • Mount Sinai Hospital
      New York City, New York, United States
  • 2011
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2004–2011
    • Technische Universiteit Eindhoven
      • • Department of Biomedical Engineering
      • • Research Group Biomedical NMR
      Eindhoven, North Brabant, Netherlands
  • 1999–2010
    • Maastricht Universitair Medisch Centrum
      • Central Diagnostic Laboratory
      Maestricht, Limburg, Netherlands
  • 1998–2010
    • Maastricht University
      • • GROW School for Oncology & Developmental Biology
      • • Department of Pathology
      • • Interne Geneeskunde
      Maastricht, Provincie Limburg, Netherlands
    • University of Groningen
      • Department of Rheumatology and Clinical Immunology
      Groningen, Province of Groningen, Netherlands
  • 2008
    • Boston Children's Hospital
      Boston, Massachusetts, United States
  • 2003–2006
    • University of Minnesota Duluth
      • Department of Chemistry and Biochemistry
      Duluth, MN, United States
  • 2000–2005
    • University of Minnesota Twin Cities
      • • Department of Biochemistry, Molecular Biology and Biophysics (CBS)
      • • Department of Pharmacology
      Minneapolis, MN, United States
  • 2001
    • University of Amsterdam
      Amsterdamo, North Holland, Netherlands
  • 1996–1998
    • University Medical Center Utrecht
      Utrecht, Utrecht, Netherlands