The presence of wild type p53 in hematological cancers improves the efficacy of combinational therapy targeting metabolism

Allende-Vega, Nerea; Krzywińska, Ewelina; Orecchioni, Stefania; López-Royuela, Nuria; Reggiani, Francesca; Talarico, Giovanna; Rossi, Jean François; Rossignol, Rodrigue; Hicheri, Yosr; Cartron, Guillaume; Bertolini, Francesco; Martín, Vicente

doi:10.18632/oncotarget.4653

Cited by 32 publications

(106 citation statements)

References 59 publications

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“…GSK621-mediated cytotoxicity requires mTORC1 activation, which is unique to AML cells and involves the eiF2a/ATF4 signaling pathway [129]. Other MAPK activators, such as the metabolic modulator dicholoroacetate [130] and the antidiabetic drug metformin [131] exhibit antileukemic activity.…”

Section: Mitochondrial Alterations In Aml Cellsmentioning

confidence: 99%

Oxidative stress and hypoxia in normal and leukemic stem cells

Testa

Labbaye

Castelli

et al. 2016

Experimental Hematology

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The main hematopoietic stem cell (HSC) functions, self-renewal and differentiation, are finely regulated by both intrinsic mechanisms such as transcriptional and epigenetic regulators and extrinsic signals originating in the bone marrow microenvironment (HSC niche) or in the body (humoral mediators). The interaction between regulatory signals and cellular metabolism is an emerging area. Several metabolic pathways function differently in HSCs compared with progenitors and differentiated cells. Hypoxia, acting through hypoxia-inducing factors, has emerged as a key regulator of stem cell biology and acts by maintaining HSC quiescence and a condition of metabolic dormancy based on anaerobic glycolytic energetic metabolism, with consequent low production reactive oxygen species (ROS) and high antioxidant defense. Hematopoietic cell differentiation is accompanied by changes in oxidative metabolism (decrease of anaerobic glycolysis and increase of oxidative phosphorylation) and increased levels of ROS. Leukemic stem cells, defined as the cells that initiate and maintain the leukemic process, show peculiar metabolic properties in that they are more dependent on oxidative respiration than on glycolysis and are more sensitive to oxidative stress than normal HSCs. Several mitochondrial abnormalities have been described in acute myeloid leukemia (AML) cells, explaining the shift to aerobic glycolysis observed in these cells and offering the unique opportunity for therapeutic metabolic targeting. Finally, frequent mutations of the mitochondrial isocitrate dehydrogenase-2 (IDH2) enzyme are observed in AML cells, in which the mutated enzyme acts as an oncogenic driver and can be targeted using specific inhibitors under clinical evaluation with promising results.

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Section: Mitochondrial Alterations In Aml Cellsmentioning

confidence: 99%

Oxidative stress and hypoxia in normal and leukemic stem cells

Testa

Labbaye

Castelli

et al. 2016

Experimental Hematology

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“…Nowadays, the most accepted explanation would be that the change in carbohydrate metabolism alters lipid metabolism. In this sense, DCA, by inhibiting glycolysis, activates AMPK 9 , which inhibits cholesterol synthesis 16 , 17 leading to LDLR expression 18 , 19 . Enhanced LDLR expression is mediated by a MAPKK because the MAPKK inhibitors PD98059 18 and U0126 20 , 21 restrain it.…”

Section: Introductionmentioning

confidence: 99%

The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway

Khan

Allende-Vega

Gitenay

et al. 2017

Sci Rep

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Controlling cholesterol levels is a major challenge in human health, since hypercholesterolemia can lead to serious cardiovascular disease. Drugs that target carbohydrate metabolism can also modify lipid metabolism and hence cholesterol plasma levels. In this sense, dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, augments usage of the glycolysis-produced pyruvate in the mitochondria increasing oxidative phosphorylation (OXPHOS). In several animal models, DCA decreases plasma cholesterol and triglycerides. Thus, DCA was used in the 70 s to treat diabetes mellitus, hyperlipoproteinemia and hypercholesterolemia with satisfactory results. However, the mechanism of action remained unknown and we describe it here. DCA increases LDLR mRNA and protein levels as well as LDL intake in several cell lines, primary human hepatocytes and two different mouse models. This effect is mediated by transcriptional activation as evidenced by H3 acetylation on lysine 27 on the LDLR promoter. DCA induces expression of the MAPK ERK5 that turns on the transcription factor MEF2. Inhibition of this ERK5/MEF2 pathway by genetic or pharmacological means decreases LDLR expression and LDL intake. In summary, our results indicate that DCA, by inducing OXPHOS, promotes ERK5/MEF2 activation leading to LDLR expression. The ERK5/MEF2 pathway offers an interesting pharmacological target for drug development.

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“…Bone marrow and peripheral blood samples were obtained from patients with different hematological diseases and from healthy donors after informed consent. Cells were purified by Ficoll-Hypaque (Sigma) density-gradient centrifugation as described earlier ( Allende-Vega et al, 2015 ). Briefly, 3–6 ml of 1:2 diluted blood or 1:3 diluted bone marrow samples in RPMI were added on top of 5 ml of Histopaque.…”

Section: Introductionmentioning

confidence: 99%

“…Data and samples from patients with different hematological cancers were collected at the Oncology and Clinical Hematology Department of the CHU Montpellier, France, after patient's informed consent ( Allende-Vega et al, 2015 ). Patients were enrolled in two independent clinical programs approved by the “Comités de Protection des Personnes Sud Méditerranée I”: ref 1324 and ID-RCB: 2011-A00924-37.…”

Section: Introductionmentioning

confidence: 99%

Identification of Anti-tumor Cells Carrying Natural Killer (NK) Cell Antigens in Patients With Hematological Cancers

et al. 2015

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Natural killer (NK) cells, a cytotoxic lymphocyte lineage, are able to kill tumor cells in vitro and in mouse models. However, whether these cells display an anti-tumor activity in cancer patients has not been demonstrated. Here we have addressed this issue in patients with several hematological cancers. We found a population of highly activated CD56dimCD16+ NK cells that have recently degranulated, evidence of killing activity, and it is absent in healthy donors. A high percentage of these cells expressed natural killer cell p46-related protein (NKp46), natural-killer group 2, member D (NKG2D) and killer inhibitory receptors (KIRs) and a low percentage expressed NKG2A and CD94. They are also characterized by a high metabolic activity and active proliferation. Notably, we found that activated NK cells from hematological cancer patients have non-NK tumor cell antigens on their surface, evidence of trogocytosis during tumor cell killing. Finally, we found that these activated NK cells are distinguished by their CD45RA+RO+ phenotype, as opposed to non-activated cells in patients or in healthy donors displaying a CD45RA+RO− phenotype similar to naïve T cells. In summary, we show that CD45RA+RO+ cells, which resemble a unique NK population, have recognized tumor cells and degranulate in patients with hematological neoplasias.

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The presence of wild type p53 in hematological cancers improves the efficacy of combinational therapy targeting metabolism

Cited by 32 publications

References 59 publications

Oxidative stress and hypoxia in normal and leukemic stem cells

Oxidative stress and hypoxia in normal and leukemic stem cells

The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway

Identification of Anti-tumor Cells Carrying Natural Killer (NK) Cell Antigens in Patients With Hematological Cancers

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