Arjan W Griffioen

VU University Medical Center, Amsterdamo, North Holland, Netherlands

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Publications (247)1303.49 Total impact

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    ABSTRACT: We describe a protocol for the discovery of synergistic drug combinations for the treatment of disease. Synergistic drug combinations lead to the use of drugs at lower doses, which reduces side effects and can potentially lead to reduced drug resistance, while being clinically more effective than the individual drugs. To cope with the extremely large search space for these combinations, we developed an efficient combinatorial drug screening method called the Feedback System Control (FSC) technique. Starting with a broad selection of drugs, the method follows an iterative approach of experimental testing in a relevant bioassay and analysis of the results by FSC. First, the protocol uses a cell viability assay to generate broad dose-response curves to assess the efficacy of individual compounds. These curves are then used to guide the dosage input of each drug to be tested in combination. Data from applied drug combinations are input into the differential evolution (DE) algorithm, which predicts new combinations to be tested in vitro. This process identifies optimal drug-dose combinations, while saving orders of magnitude in experimental effort. The complete optimization process is estimated to take ∼4 weeks. FSC does not require insight into the disease mechanism, and it has therefore been applied to find combination therapies for many different pathologies, including cancer and infectious diseases, and it has also been used in organ transplantation.
    Full-text · Article · Jan 2016 · Nature Protocols

  • No preview · Article · Dec 2015
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    Full-text · Article · Dec 2015
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    ABSTRACT: Angiogenesis is a prerequisite for solid tumors to grow and metastasize, providing oxygen and nutrients to the tumor site. The protein galectin-1 has been identified to be overexpressed on tumor vasculature and represents an interesting target for anti-angiogenic therapy, as well as in molecular imaging. Therefore, the galectin-1-binding peptide Anginex was modified for radiolabeling using 111In. In vitro, 111In-Ax showed significantly more binding to galectin-1-positive EC-RF24 and MDA-MB-231-LITG cells than to galectin-1-negative LS174T cells and association with EC-RF24 cells was reduced in the presence of excess native Anginex. However, ex vivo biodistribution profiles showed little tumor uptake of 111In-Ax and extensive accumulation in non-target organs. Although this study shows the ease of modification of the therapeutic peptide Anginex and favorable characteristics in vitro, in vivo assessment of the tracer revealed negligible tumor targeting. Hence, the strategy we employed lends little support for successful non-invasive imaging of tumor angiogenesis using this peptide.
    No preview · Article · Nov 2015 · Anticancer research
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    ABSTRACT: The back cover picture shows the structure of an osmium compound that displays selective cytotoxicity towards cancerous cells but with essentially no cytotoxicity towards noncancerous human embryonic kidney cells and human endothelial cells. In vivo, the compound disrupts vascularization to a considerably greater extent than the clinically applied drug sunitinib and in the absence of observed side effects. More details can be found in the Full Paper by P. J. Dyson et al. on page 1539 in Issue 9, 2015. (DOI: 10.1002/cmdc.201500221).
    Full-text · Article · Sep 2015 · ChemMedChem
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    ABSTRACT: A major key to improvement of cancer therapy is the combination of drugs. Mixing drugs that already exist on the market may offer an attractive alternative. Here we report on a new model-based streamlined feedback system control (s-FSC) method, based on a design of experiment approach, for rapidly finding optimal drug mixtures with minimal experimental effort. We tested combinations in an in vitro assay for the viability of a renal cell adenocarcinoma (RCC) cell line, 786-O. An iterative cycle of in vitro testing and s-FSC analysis was repeated a few times until an optimal low dose combination was reached. Starting with ten drugs that target parallel pathways known to play a role in the development and progression of RCC, we identified the best overall drug combination, being a mixture of four drugs (axitinib, erlotinib, dasatinib and AZD4547) at low doses, inhibiting 90% of cell viability. The removal of AZD4547 from the optimized drug combination resulted in 80% of cell viability inhibition, while still maintaining the synergistic interaction. These optimized drug combinations were significantly more potent than monotherapies of all individual drugs.
    Full-text · Article · Aug 2015 · Scientific Reports
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    ABSTRACT: Aggressive tumor cells can obtain the ability to transdifferentiate into cells with endothelial features and thus form vasculogenic networks. This phenomenon, called vasculogenic mimicry (VM), is associated with increased tumor malignancy and poor clinical outcome. To identify novel key molecules implicated in the process of vasculogenic mimicry, microarray analysis was performed to compare gene expression profiles of aggressive (VM+) and non-aggressive (VM-) cells derived from Ewing sarcoma and breast carcinoma. We identified the CD44/c-Met signaling cascade as heavily relevant for vasculogenic mimicry. CD44 was at the center of this cascade, and highly overexpressed in aggressive tumors. Both CD44 standard isoform and its splice variant CD44v6 were linked to increased aggressiveness in VM. Since VM is most abundant in Ewing sarcoma tumors functional analyses were performed in EW7 cells. Overexpression of CD44 allowed enhanced adhesion to its extracellular matrix ligand hyaluronic acid. CD44 expression also facilitated the formation of vasculogenic structures in vitro, as CD44 knockdown experiments repressed migration and vascular network formation. From these results and the observation that CD44 expression is associated with vasculogenic structures and blood lakes in human Ewing sarcoma tissues, we conclude that CD44 increases aggressiveness in tumors through the process of vasculogenic mimicry.
    Preview · Article · Aug 2015 · Oncotarget

  • No preview · Article · Aug 2015 · Cancer Research
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    ABSTRACT: Osmium compounds are attracting increasing attention as potential anticancer drugs. In this context, a series of bifunctional organometallic osmium(II)-p-cymene complexes functionalized with alkyl or perfluoroalkyl groups were prepared and screened for their antiproliferative activity. Three compounds from the series display selectivity toward cancer cells, with moderate cytotoxicity observed against human ovarian carcinoma (A2780) cells, whereas no cytotoxicity was observed on non-cancerous human embryonic kidney (HEK-293) cells and human endothelial (ECRF24) cells. Two of these three cancer-cell-selective compounds induce cell death largely via apoptosis and were also found to disrupt vascularization in the chicken embryo chorioallantoic membrane (CAM) model. Based on these promising properties, these compounds have potential clinical applications. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    Full-text · Article · Jul 2015 · ChemMedChem
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    ABSTRACT: Two bifunctional ruthenium(II)-p-cymene complexes with perfluorinated side chains, attached via pyridine ligands, have been evaluated in a series of in vitro and in vivo assays. Their effects on human endothelial (ECRF24 and HUVEC) cells, non-cancerous human embryonic kidney (HEK-293) cells and various human tumor cells were investigated. The complex with the shorter chain, 1, inhibits the proliferation of the tumor cell lines and ECRF24, whereas 2, selectively inhibits ECRF24 and HUVEC proliferation. Neither of them inhibits the migration of ECRF24 cells whereas both compounds inhibit sprout formation in HUVEC cells. Using three preclinical models, i.e. vasculature formation in the chorioallantoic membrane (CAM) of the chicken embryo, human A2780 ovarian carcinoma tumors xenografted on the CAM and human LS174T colorectal adenocarcinoma tumors grown in athymic mice, the angiostatic and anticancer activities of these two complexes were studied. Overall, 1 inhibited tumor growth predominantly through an anticancer effect whereas 2 inhibited tumor growth predominately via an anti-angiogenic mechanism.
    Full-text · Article · Jul 2015 · Molecular Pharmaceutics
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    Full-text · Dataset · May 2015
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    ABSTRACT: Glycosaminoglycan (GAG) polysaccharides have been implicated in a variety of cellular processes, and alterations in their amount and structure have been associated with diseases such as cancer. In this study, we probed 11 sugar analogs for their capacity to interfere with GAG biosynthesis. One analog, with a modification not directly involved in the glycosidic bond formation, 6F-N-acetyl-d-galactosamine (GalNAc) (Ac3), was selected for further study on its metabolic and biologic effect. Treatment of human ovarian carcinoma cells with 50 μM 6F-GalNAc (Ac3) inhibited biosynthesis of GAGs (chondroitin/dermatan sulfate by ∼50-60%, heparan sulfate by ∼35%), N-acetyl-d-glucosamine (GlcNAc)/GalNAc containing glycans recognized by the lectins Datura stramonium and peanut agglutinin (by ∼74 and ∼43%, respectively), and O-GlcNAc protein modification. With respect to function, 6F-GalNAc (Ac3) treatment inhibited growth factor signaling and reduced in vivo angiogenesis by ∼33%. Although the analog was readily transformed in cells into the uridine 5'-diphosphate (UDP)-activated form, it was not incorporated into GAGs. Rather, it strongly reduced cellular UDP-GalNAc and UDP-GlcNAc pools. Together with data from the literature, these findings indicate that nucleotide sugar depletion without incorporation is a common mechanism of sugar analogs for inhibiting GAG/glycan biosynthesis.-Van Wijk, X. M., Lawrence, R., Thijssen, V. L., van den Broek, S. A., Troost, R., van Scherpenzeel, M., Naidu, N, Oosterhof, A., Griffioen, A. W., Lefeber, D. J., van Delft, F. L., van Kuppevelt, T. H. A common sugar-nucleotide-mediated mechanism of inhibition of (glycosamino)glycan biosynthesis, as evidenced by 6F-GalNAc (Ac3). © FASEB.
    Full-text · Article · Apr 2015 · The FASEB Journal
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    Full-text · Dataset · Apr 2015
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    ABSTRACT: The concept of antiangiogenic therapy in cancer treatment has led to the approval of different agents, most of them targeting the well known vascular endothelial growth factor pathway. Despite promising results in preclinical studies, the efficacy of antiangiogenic therapy in the clinical setting remains limited. Recently, awareness has emerged on resistance to antiangiogenic therapies. It has become apparent that the intricate complex interplay between tumors and stromal cells, including endothelial cells and associated mural cells, allows for escape mechanisms to arise that counteract the effects of these targeted therapeutics. Here, we review and discuss known and novel mechanisms that contribute to resistance against antiangiogenic therapy and provide an outlook to possible improvements in therapeutic approaches. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
    Full-text · Article · Apr 2015 · Pharmacological reviews
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    ABSTRACT: Drug combinations can improve angiostatic cancer treatment efficacy and enable the reduction of side effects and drug resistance. Combining drugs is non-trivial due to the high number of possibilities. We applied a feedback system control (FSC) technique with a population-based stochastic search algorithm to navigate through the large parametric space of nine angiostatic drugs at four concentrations to identify optimal low-dose drug combinations. This implied an iterative approach of in vitro testing of endothelial cell viability and algorithm-based analysis. The optimal synergistic drug combination, containing erlotinib, BEZ-235 and RAPTA-C, was reached in a small number of iterations. Final drug combinations showed enhanced endothelial cell specificity and synergistically inhibited proliferation (p < 0.001), but not migration of endothelial cells, and forced enhanced numbers of endothelial cells to undergo apoptosis (p < 0.01). Successful translation of this drug combination was achieved in two preclinical in vivo tumor models. Tumor growth was inhibited synergistically and significantly (p < 0.05 and p < 0.01, respectively) using reduced drug doses as compared to optimal single-drug concentrations. At the applied conditions, single-drug monotherapies had no or negligible activity in these models. We suggest that FSC can be used for rapid identification of effective, reduced dose, multi-drug combinations for the treatment of cancer and other diseases. Electronic supplementary material The online version of this article (doi:10.1007/s10456-015-9462-9) contains supplementary material, which is available to authorized users.
    Full-text · Article · Mar 2015 · Angiogenesis
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    ABSTRACT: The tumour microenvironment comprises a network of immune response and vascularization factors. From this network, we identified immunological and vascularization gene expression clusters and the correlations between the clusters. We subsequently determined which factors were correlated with patient survival in cervical carcinoma. The expression of 42 genes was investigated in 52 fresh frozen squamous cervical cancer samples by qRT-PCR. Weighted gene co-expression network analysis and mixed-model analyses were performed to identify gene expression clusters. Correlations and survival analyses were further studied at expression cluster and single gene level. We identified four immune response clusters: ‘T cells’ (CD3E/CD8A/TBX21/IFNG/FOXP3/IDO1), ‘Macrophages’ (CD4/CD14/CD163), ‘Th2’ (IL4/IL5/IL13/IL12) and ‘Inflammation’ (IL6/IL1B/IL8/IL23/IL10/ARG1) and two vascularization clusters: ‘Angiogenesis’ (VEGFA/FLT1/ANGPT2/ PGF/ICAM1) and ‘Vessel maturation’ (PECAM1/VCAM1/ANGPT1/SELE/KDR/LGALS9). The ‘T cells’ module was correlated with all modules except for ‘Inflammation’, while ‘Inflammation’ was most significantly correlated with ‘Angiogenesis’ (p < 0.001). High expression of the ‘T cells’ cluster was correlated with earlier TNM stage (p = 0.007). High CD3E expression was correlated with improved disease-specific survival (p = 0.022), while high VEGFA expression was correlated with poor disease-specific survival (p = 0.032). Independent predictors of poor disease-specific survival were IL6 (hazard ratio = 2.3, p = 0.011) and a high IL6/IL17 ratio combined with low IL5 expression (hazard ratio = 4.2, p = 0.010). ‘Inflammation’ marker IL6, especially in combination with low levels of IL5 and IL17, was correlated with poor survival. This suggests that IL6 promotes tumour growth, which may be suppressed by a Th17 and Th2 response. Measuring IL6, IL5 and IL17 expression may improve the accuracy of predicting prognosis in cervical cancer.
    Full-text · Article · Mar 2015 · Molecular Cancer
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    ABSTRACT: The combination of radiotherapy with sunitinib is clinically hampered by rare but severe side effects and varying results with respect to clinical benefit. We studied different scheduling regimes and dose reduction in sunitinib and radiotherapy in preclinical tumor models to improve potential outcome of this combination treatment strategy. The chicken chorioallantoic membrane (CAM) was used as an angiogenesis in vivo model and as a xenograft model with human tumor cells (HT29 colorectal adenocarcinoma, OE19 esophageal adenocarcinoma). Treatment consisted of ionizing radiation (IR) and sunitinib as single therapy or in combination, using different dose-scheduling regimes. Sunitinib potentiated the inhibitory effect of IR (4 Gy) on angiogenesis. In addition, IR (4 Gy) and sunitinib (4 days of 32.5 mg/kg per day) inhibited tumor growth. Ionizing radiation induced tumor cell apoptosis and reduced proliferation, whereas sunitinib decreased tumor angiogenesis and reduced tumor cell proliferation. When IR was applied before sunitinib, this almost completely inhibited tumor growth, whereas concurrent IR was less effective and IR after sunitinib had no additional effect on tumor growth. Moreover, optimal scheduling allowed a 50% dose reduction in sunitinib while maintaining comparable antitumor effects. This study shows that the therapeutic efficacy of combination therapy improves when proper dose-scheduling is applied. More importantly, optimal treatment regimes permit dose reductions in the angiogenesis inhibitor, which will likely reduce the side effects of combination therapy in the clinical setting. Our study provides important leads to optimize combination treatment in the clinical setting. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
    Full-text · Article · Mar 2015 · Cancer Medicine
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    ABSTRACT: Following the identification of [Ru(η6-p-cymene)Cl2(1H,1H,2H,2H-perfluorodecyl-3-(pyridin-3-yl)propanoate)], a ruthenium(II)-arene complex with a perfluoroalkyl-modified ligand, that displays remarkable in vitro cancer cell selectivity, a series of structurally related compounds were designed. In the new derivatives, the p-cymene ring and/or the chloride ligands are substituted by other ligands to modulate the steric bulk or aquation kinetics. The new compounds were evaluated in both in vitro (cytotoxicity and migration assays) and in vivo (chicken chorioallantoic membrane) models and were found to exhibit potent antivascular effects.
    Full-text · Article · Mar 2015 · Journal of Medicinal Chemistry
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    Victor L Thijssen · Roy Heusschen · Jo Caers · Arjan W Griffioen
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    ABSTRACT: Galectins are a family of proteins that bind to specific glycans thereby deciphering the information captured within the glycome. In the last two decades, several galectin family members have emerged as versatile modulators of tumor progression. This has initiated the development and preclinical assessment of galectin-targeting compounds. With the first compounds now entering clinical trials it is pivotal to gain insight in the diagnostic and prognostic value of galectins in cancer as this will allow a more rational selection of the patients that might benefit most from galectin-targeted therapies. Here, we present a systematic review of galectin expression in human cancer patients. Malignant transformation is frequently associated with altered galectin expression, most notably of galectin-1 and galectin-3. In most cancers, increased galectin-1 expression is associated with poor prognosis while elevated galectin-9 expression is emerging as a marker of favorable disease outcome. The prognostic value of galectin-3 appears to be tumor type dependent and the other galectins require further investigation. Regarding the latter, additional studies using larger patient cohorts are essential to fully unravel the diagnostic and prognostic value of galectin expression. Furthermore, to better compare different findings, consensus should be reached on how to assess galectin expression, not only with regard to localization within the tissue and within cellular compartments but also regarding alternative splicing and genomic variations. Finally, linking galectin expression and function to aberrant glycosylation in cancer cells will improve our understanding of how these versatile proteins can be exploited for diagnostic, prognostic and even therapeutic purposes in cancer patients. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Mar 2015 · Biochimica et Biophysica Acta
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    ABSTRACT: Hyperthermia used as an adjuvant with chemotherapy is highly promising in the treatment of certain cancers. Currently, the small molecule drugs used in combination with hyperthermia were not designed for this application. Herein, we report the evaluation of a chlorambucil and a ruthenium compound modified with a long fluorous chain, which exhibit thermoresponsive activity in colorectal adenocarcinoma xenografts in athymic mice in combination with mild hyperthermia (42°C). Intraperitoneal injection of the derivatives followed by local hyperthermia showed a synergistic tumor growth reduction by 79% and 90% for the chlorambucil and ruthenium-based derivatives, respectively, with the latter exhibiting a higher synergy in combination with hyperthermia compared to the monotherapies. Histological analysis shows that both derivatives in combination with hyperthermia significantly decrease the number of proliferating tumor cells.
    Full-text · Article · Mar 2015 · Chemical Science

Publication Stats

9k Citations
1,303.49 Total Impact Points

Institutions

  • 2010-2015
    • VU University Medical Center
      • Department of Pathology
      Amsterdamo, North Holland, Netherlands
  • 2009-2015
    • VU University Amsterdam
      • Department of Medical Oncology
      Amsterdamo, North Holland, Netherlands
  • 1997-2011
    • Maastricht University
      • • GROW School for Oncology & Developmental Biology
      • • Department of Pathology
      • • Department of Internal Medicine
      Maestricht, Limburg, Netherlands
  • 2006-2009
    • Technische Universiteit Eindhoven
      • Department of Biomedical Engineering
      Eindhoven, North Brabant, Netherlands
    • Leiden University
      Leyden, South Holland, Netherlands
    • University of Minnesota Duluth
      • Department of Chemistry and Biochemistry
      Duluth, MN, United States
  • 1998-2008
    • Maastricht Universitair Medisch Centrum
      • Central Diagnostic Laboratory
      Maestricht, Limburg, Netherlands
  • 1996-2006
    • University Medical Center Utrecht
      • Laboratory of Experimental Cardiology
      Utrecht, Utrecht, Netherlands
    • Utrecht University
      • Department of Medical Oncology
      Utrecht, Utrecht, Netherlands
  • 2004
    • Delft University of Technology
      Delft, South Holland, Netherlands