Hypoxia promotes chemoresistance in acute lymphoblastic leukemia cell lines by modulating death signaling pathways

International audienceBackground: Several studies show that bone marrow (BM) microenvironment and hypoxia condition can promote the survival of leukemic cells and induce resistance to anti-leukemic drugs. However, the molecular mechanism for chemoresistance by hypoxia is not fully understood.Methods: In the present study, we investigated the effect of hypoxia on resistance to two therapies, methotrexate (MTX) and prednisolone (PRD), in two cell models for acute lymphoblastic leukemia (ALL). To look for an implication of hypoxia in chemoresistance, cell viability, total cell density and cell proliferation were analyzed. Survival and death signaling pathways were also screened by "reverse phase protein array" (RPPA) and western blotting experiments conducted on selected proteins to confirm the results.Results: We found that hypoxia promotes chemoresistance in both ALL cell lines. The induction of drug-resistance by hypoxia was not associated with an increase in total cell density nor an increase in cell proliferation. Using RPPA, we show that chemoresistance induced by hypoxia was mediated through an alteration of cell death signaling pathways. This protective effect of hypoxia seems to occur via a decrease in pro-apoptotic proteins and an increase in anti-apoptotic proteins. The results were confirmed by immunoblotting. Indeed, hypoxia is able to modulate the expression of anti-apoptotic proteins independently of chemotherapy while a pro-apoptotic signal induced by a chemotherapy is not modulated by hypoxia.Conclusions: Hypoxia is a factor in leukemia cell resistance and for two conventional chemotherapies modulates cell death signaling pathways without affecting total cell density or cell proliferation

What Role for Angiogenesis in Childhood Acute Lymphoblastic Leukaemia?

The role of angiogenesis in acute leukaemia has been discussed since the cloning of the gene of vascular endothelial growth factor (VEGF) from the acute myelogenous leukemia cell line (HL60) and, thereafter, when the first studies reported increased bone marrow vascularity and elevation of angiogenic cytokines in acute lymphoblastic leukaemia (ALL). VEGF and basic fibroblast growth factor (bFGF) are the major proangiogenic cytokines that have been studied, and evaluation of their prognostic impact in childhood ALL has been reported in several studies, though with controversial results. The antiangiogenic response, contributing to the angiogenic balance, has scarcely been reported. The origin of the factors, their prognostic value, and their relevance as good markers of what really happens in the bone marrow are discussed in this paper. The place of antiangiogenic drugs in ALL has to be defined in the global treatment strategy

Continuous cerebroventricular administration of dopamine: A new treatment for severe dyskinesia in Parkinson’s disease?

In Parkinson’s disease (PD) depletion of dopamine in the nigro-striatal pathway is a main pathological hallmark that requires continuous and focal restoration. Current predominant treatment with intermittent oral administration of its precursor, Levodopa (l-dopa), remains the gold standard but pharmacological drawbacks trigger motor fluctuations and dyskinesia. Continuous intracerebroventricular (i.c.v.) administration of dopamine previously failed as a therapy because of an inability to resolve the accelerated dopamine oxidation and tachyphylaxia. We aim to overcome prior challenges by demonstrating treatment feasibility and efficacy of continuous i.c.v. of dopamine close to the striatum. Dopamine prepared either anaerobically (A-dopamine) or aerobically (O-dopamine) in the presence or absence of a conservator (sodium metabisulfite, SMBS) was assessed upon acute MPTP and chronic 6-OHDA lesioning and compared to peripheral l-dopa treatment. A-dopamine restored motor function and induced a dose dependent increase of nigro-striatal tyrosine hydroxylase positive neurons in mice after 7 days of MPTP insult that was not evident with either O-dopamine or l-dopa. In the 6-OHDA rat model, continuous circadian i.c.v. injection of A-dopamine over 30 days also improved motor activity without occurrence of tachyphylaxia. This safety profile was highly favorable as A-dopamine did not induce dyskinesia or behavioral sensitization as observed with peripheral l-dopa treatment. Indicative of a new therapeutic strategy for patients suffering from l-dopa related complications with dyskinesia, continuous i.c.v. of A-dopamine has greater efficacy in mediating motor impairment over a large therapeutic index without inducing dyskinesia and tachyphylaxia

International Science Foresight Workshop: Global Challenges and Research Gaps. The Royaumont process.

How scientists might better contribute to SDGs in the land sector? At the invitation of INRAE, a group of high-level international experts delivers a comprehensive and systemic approach

An Overview of the Ethics of Eating and Drinking

Eating and drinking are ethical acts. When we make decisions about what to eat and what not to, we are making decisions that impact our own health, the well-being of those who work in the food system, animal welfare, and the environment. Food ethics is the interdisciplinary study of how what we eat – including the way it is produced, distributed, marketed, prepared, and ultimately consumed – impacts human, animal, and planetary health and well-being. Food ethics also analyses the justice or fairness of these impacts. Food ethics raises many difficult questions that do not always have clear or easy answers, such as how do we produce enough food to feed everyone well and equitably; how do we ensure that everyone has access to high-quality, nutritious food that is culturally appropriate; how do we do this in a way that treats workers fairly and respectfully, is considerate of animal welfare, and is environmentally sustainable; and how do we shift power across the food system in favor of the public good over multinational food companies. This chapter will explore these questions and more, hopefully encouraging thoughtful discussions and potential solutions for the future

Food security and storage in the Middle East and North Africa

In times of highly volatile commodity markets, governments often try to protect their populations from rapidly-rising food prices, which can be particularly harsh for the poor. A potential solution for food-deficit countries is to hold strategic reserves, which can be called on when international prices spike. But how large should strategic stockpiles be? This paper develops a dynamic storage model for wheat in the Middle East and North Africa (MENA) region, where imported wheat dominates the average diet. The paper uses the model to analyze a strategy that sets aside wheat stockpiles, which can be used when needed to keep domestic prices below a targeted price. This paper shows that if the target is set high and reserves are adequate, the strategy can be effective and robust. Contrary to most interventions, strategic storage policies are counter-cyclical and, when the importing region is sufficiently large, a regional policy can smooth global prices. This paper shows that this is the case for the MENA region. Nevertheless, the policy is more costly than the pro-cyclical policy of a targeted intervention that directly offsets high prices with a subsidy similar to food stamps.Lorsque les prix des matières premières sont très volatiles, les gouvernements essayent généralement de protéger leur population d'une augmentation rapide des prix agricoles. Une solution potentielle pour des pays importateurs nets de produits agricoles est de maintenir des stocks de réserve, qui peuvent être utilisés lorsque les prix mondiaux augmentent fortement. Mais quelle doit être la taille de telles réserves? Cet article développe un modèle dynamique de stockage pour le marché du blé dans la région Moyen Orient et Afrique du Nord, où le blé importé représente une part prépondérante de l'alimentation. Ce modèle est utilisé pour analyser une stratégie dans laquelle des stocks servent à maintenir les prix domestiques en dessous d'une cible. Nous montrons que si la cible est choisie suffisamment haute et les réserves sont adéquates, la stratégie peut être effective et robuste. Contrairement à la plupart des interventions, une politique de stockage stratégique est contra-cyclique et, lorsque la région importatrice est suffisamment large, une telle politique régionale peut lisser les variations du prix mondial. C'est le cas, dans ce travail, pour la région Moyen Orient et Afrique du Nord. Néanmoins, cette politique est plus coûteuse qu'une politique d'intervention ciblée qui limitent directement les hausses de prix par une subvention

Additional file 6: Figure S5. of Hypoxia promotes chemoresistance in acute lymphoblastic leukemia cell lines by modulating death signaling pathways

RPPA analysis of Reh cell lines treated with PRD. Signal intensities were normalized by Z-score and signals were used for a hierarchical cluster analysis. A black color indicates that protein from Reh cells treated with several concentrations of PRD in normoxia versus hypoxia, matches the medium expression level calculated for a specific protein in a particular experimental condition. Higher level expression than mean is shown as a red color, and a green color refers to a lower level expression than mean. Protein names are listed below and experimental conditions are mentioned on the right-hand side. All antibodies used for RPPA were validated by Western blot. All antibodies are listed in Additional file 7: Table S1. (DOCX 148 kb

Additional file 3: Figure S2. of Hypoxia promotes chemoresistance in acute lymphoblastic leukemia cell lines by modulating death signaling pathways

RPPA analysis of Nalm-6 cell lines treated with MTX. Signal intensities were normalized by Z-score and signals were used for a hierarchical cluster analysis. A black color indicates that protein from Nalm-6 cells treated with several concentrations of MTX in normoxia versus hypoxia, matches the medium expression level calculated for a specific protein in a particular experimental condition. Higher level expression than mean is shown as a red color, and a green color refers to a lower level expression than mean. Protein names are listed below and experimental conditions are mentioned on the right-hand side. All antibodies used for RPPA were validated by Western blot. All antibodies are listed in Additional file 7: Table S1. (DOCX 145 kb

Additional file 1: Protocol S1. of Hypoxia promotes chemoresistance in acute lymphoblastic leukemia cell lines by modulating death signaling pathways

RPPA full protocol. (DOCX 15 kb