Showing papers by "Huib N. Caron published in 2016"
TL;DR: It is shown that neuroblastoma cells might survive ABT199 treatment due to its acute upregulation of the anti-apoptotic BCL-2 family protein myeloid cell leukaemia sequence 1 (M CL-1) and BIM sequestration by MCL-1.
Abstract: // Laurel T. Bate-Eya 1 , Ilona J.M. den Hartog 1 , Ida van der Ploeg 1 , Linda Schild 1 , Jan Koster 1 , Evan E. Santo 1 , Ellen M. Westerhout 1 , Rogier Versteeg 1 , Huib N. Caron 2 , Jan J. Molenaar 1 , M. Emmy M. Dolman 1 1 Department of Oncogenomics, University of Amsterdam, Amsterdam, The Netherlands 2 Department of Pediatric Oncology, Emma Kinderziekenhuis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Correspondence to: M. Emmy M. Dolman, e-mail: memdolman@gmail.com Keywords: neuroblastoma, ABT199, BCL-2, MCL-1, resistance Received: November 26, 2015 Accepted: March 18, 2016 Published: April 1, 2016 ABSTRACT The anti-apoptotic protein B cell lymphoma/leukaemia 2 ( BCL-2 ) is highly expressed in neuroblastoma and plays an important role in oncogenesis. In this study, the selective BCL-2 inhibitor ABT199 was tested in a panel of neuroblastoma cell lines with diverse expression levels of BCL-2 and other BCL-2 family proteins. ABT199 caused apoptosis more potently in neuroblastoma cell lines expressing high BCL-2 and BIM/BCL-2 complex levels than low expressing cell lines. Effects on cell viability correlated with effects on BIM displacement from BCL-2 and cytochrome c release from the mitochondria. ABT199 treatment of mice with neuroblastoma tumors expressing high BCL-2 levels only resulted in growth inhibition, despite maximum BIM displacement from BCL-2 and the induction of a strong apoptotic response. We showed that neuroblastoma cells might survive ABT199 treatment due to its acute upregulation of the anti-apoptotic BCL-2 family protein myeloid cell leukaemia sequence 1 (MCL-1) and BIM sequestration by MCL-1. In vitro inhibition of MCL-1 sensitized neuroblastoma cell lines to ABT199, confirming the pivotal role of MCL-1 in ABT199 resistance. Our findings suggest that neuroblastoma patients with high BCL-2 and BIM/BCL-2 complex levels might benefit from combination treatment with ABT199 and compounds that inhibit MCL-1 expression.
47 citations
TL;DR: BM positivity was associated with unfavourable biological factors and might represent more aggressive tumours and patients with qPCR positive BM should not be upstaged, because of very few systemic events in the cohort.
10 citations
TL;DR: Although it could not explain the reduced complement functionality under all conditions, a strong effect was observed following high-dose methotrexate or ifosfamide, some of which associated with certain chemotherapeutic drugs.
Abstract: Introduction: To date, oncology patients are more dependent on non-cellular host defense against pathogens due to intensive (chemo)therapy-related bone marrow suppression. Since data on complement functionality in oncology patients are limited, we aimed to investigate the innate complement function in relation to the type of malignancy and therapy in a longitudinal cohort of patients. Methods: A large single-center, prospective non-intervention study was conducted, in which blood samples were taken from patients before, during and after treatment with chemotherapy and/or subsequent admittance for (febrile) neutropenia. Results/findings: Analysis of 48 patients showed a high percentage of defects in complement activity of the alternative pathway (19.1%), the classical pathway (4.3%) or both (42.6%). Post-hoc analysis of six different treatment protocols with more than 3 patients each showed distinct effects of specific therapies. Whereas patients treated according to the Ewing, EpSSG-rhabdomyosarcoma or SIOP CNS germ cell tumor protocol showed no defects, patients treated according to the ALL-11 (leukemia), the EURAMOS I (osteosarcoma) or the ACNS (medulloblastoma) protocols showed an almost universal reduction in complement function. Although we could not explain the reduced complement functionality under all conditions, a strong effect was observed following high-dose methotrexate or ifosfamide. Conclusion: Acquired complement defects were commonly observed in more than 50% of oncology patients, some of which associated with certain chemotherapeutic drugs. Additional studies are needed to determine the clinical and therapeutic context of complement defects and their possible effect on treatment outcome or the increased risk of infection.
8 citations