J H Stegehuis

Universitair Medisch Centrum Groningen, Groningen, Groningen, Netherlands

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Publications (5)22.22 Total impact

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    ABSTRACT: tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) initiates apoptosis in tumor cells upon binding to its cognate agonistic receptors, death receptors 4 and 5 (DR4 and DR5). The activity of the insulin-like growth factor 1 (IGF-1) survival pathway is often increased in cancer, influencing both cell proliferation and apoptosis. We hypothesized that inhibiting the IGF-1 receptor (IGF-1R) using NVP-AEW541, a small molecular weight tyrosine kinase inhibitor of the IGF-1R, could increase death receptor (DR)-mediated apoptosis in colon cancer cells. the analyses were performed by caspase assay, flow cytometry, Western blotting, immunoprecipitation and fluorescent microscopy. preincubation with NVP-AEW541 surprisingly decreased apoptosis induced by recombinant human TRAIL (rhTRAIL) or an agonistic DR4 antibody while sensitivity to an agonistic DR5 antibody was increased. NVP-AEW541 could inhibit IGF-1-induced activation of the phosphatidylinositol 3-kinase (PI3K) pathway. The effects of the PI3K inhibitor LY294002 on TRAIL-induced apoptosis were similar to those of NVP-AEW541, further supporting a role for IGF-1R-mediated activation of PI3K. We show that PI3K inhibition enhances DR5-mediated caspase 8 processing but also lowers DR4 membrane expression and DR4-mediated caspase 8 processing. Inhibition of PI3K reduced rhTRAIL sensitivity independently of the cell line preference for either DR4- or DR5-mediated apoptosis signaling. our study indicates that individual effects on DR4 and DR5 apoptosis signaling should be taken into consideration when combining DR-ligands with PI3K inhibition.
    Analytical cellular pathology (Amsterdam) 10/2010; 33(5):229-44. · 0.92 Impact Factor
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    ABSTRACT: Non-small cell lung cancer (NSCLC) is a common and often fatal malignancy, diagnosed at an advanced stage in more than half of the cases. Chemo-resistance remains a major problem in the treatment of NSCLC patients with conventional chemotherapeutic agents. Therefore main research efforts are focused on the development of novel targeted agents. In this review we provide an overview on the use of TNF-related apoptosis-inducing ligand (TRAIL) receptor targeting agents in NSCLC models and in early clinical studies. Different TRAIL receptor targeting agents are available which have been tested in NSCLC models and some were tested in the clinic. The efficacy of these drugs as single agents in NSCLC models is discussed as well as different mechanisms of resistance that are found in NSCLC cell lines. In order to maximize sensitivity to TRAIL receptor targeting drugs, combined use with other drugs is of interest. The current status of tested combinations of TRAIL receptor targeting agents with other therapeutics, such as classical cytotoxics, Bcl-2 family targeting agents, proteasome inhibitors, EGFR inhibitors, histone deacetylase inhibitors and COX-2 inhibitors as well as their mechanisms in preclinical studies are discussed. Clinical studies on TRAIL targeted therapies in which NSCLC patients were included are discussed and future perspectives are considered.
    Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy 01/2010; 13(1-2):2-15. · 12.58 Impact Factor
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    ABSTRACT: The purpose of this study was to investigate possible altered chorionic vascularization patterns that are seen already in the first trimester of pregnancies that are complicated by hypertensive disorders or intrauterine growth restriction (IUGR) in the third trimester of pregnancy. After chorionic villous sampling, surplus of villi were stored, and a selection was made of pregnancies that were complicated further by hypertensive disorders (n = 26), normotensive IUGR (n = 13), and matched control subjects (n = 60). Vascular parameters of these villi were analyzed with a video-image-analysis system. In pregnancies that are complicated by early-onset hypertensive disorders and IUGR, the mean distance of the peripheral vessels to the intervillous space and the total of the distances (central and peripheral) are significantly smaller, compared with control subjects (9.3% and 13.8% for hypertensive disorders and 12.2% and 16.1% for IUGR, respectively). Differences in vascularization patterns in the placenta already in the first trimester of pregnancies that are complicated later by hypertensive disorders or IUGR confirm the hypothesis of early changes by means of more vessels and more peripheral vessels that are located in chorionic villi.
    American journal of obstetrics and gynecology 10/2009; 202(1):88.e1-7. · 3.28 Impact Factor
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    ABSTRACT: The natural occurring tumor necrosis factor related apoptosis-inducing ligand (TRAIL) induces apoptosis following binding to the two TRAIL death receptors (DRs). Its recombinant form and monoclonal antibodies against the TRAIL DRs induce cell death in a wide variety of tumor cell lines and xenografts without causing toxicity to normal cells and are therefore potential attractive anticancer agents. These agents are currently in early clinical development. The phase 1 and 2 studies showed until now limited toxicity and tumor responses have been observed. Ongoing studies focus especially on combination of these agents with other targeted therapies or cytotoxic therapies. In this review, we summarize current knowledge on these agents and highlight their potential role in the intrinsically chemotherapy-resistant glioblastomas. In addition, we discuss the mechanisms to sensitize tumors cells to rhTRAIL by combination with the proteasome inhibitor bortezomib.
    Current Opinion in Pharmacology 08/2008; 8(4):433-9. · 5.44 Impact Factor
  • Janet Henrieke Stegehuis
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    ABSTRACT: [Nog geen abstract aanwezig]