Cyclic AMP efflux inhibitors as potential therapeutic agents for leukemia

Perez, Dominique; Smagley, Yelena; Garcia, Matthew; Carter, Mark B.; Evangelisti, Annette M.; Matławska-Wasowska, Ksenia; Winter, Stuart S.; Sklar, Larry A.; Chigaev, Alexandre

doi:10.18632/oncotarget.8986

Cited by 20 publications

(19 citation statements)

References 130 publications

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“…We could identify 94 gene products and 47 molecular pathways that had close to 1 AUC scores for the ALL-normal comparison (Supplementary dataset S4, Table 1). Among those, branches of Akt signaling [24], cAMP [25], cytoplasmic and mitochondrial apoptosis [26], PTEN [27], ATM checkpoint [28], Hedgehog [29], HGF [30], GSK3 [31], Estrogen and Glucocorticoid reception [32, 33], IGF1R [34], IL2 [35], TNF [36], ILK [37], JAK-STAT [38], JNK [39], mTOR [40], TGF-beta [41], Ras [42], PPAR [43], NGF [44], VEGF [45], Wnt [46], HIF1 and Notch signaling [47] were previously reported in the literature as ALL-associated pathways. However, the identified GPCR and TRAF-associated apoptosis marker pathways were new, thus representing ~4% of the total ALL-specific pathways.…”

Section: Resultsmentioning

confidence: 99%

Molecular pathway activation features of pediatric acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) cells

Petrov

Suntsova

Mutorova

et al. 2016

Aging

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Acute lymphoblast leukemia (ALL) is characterized by overproduction of immature white blood cells in the bone marrow. ALL is most common in the childhood and has high (>80%) cure rate. In contrast, acute myeloid leukemia (AML) has far greater mortality rate than the ALL and is most commonly affecting older adults. However, AML is a leading cause of childhood cancer mortality. In this study, we compare gene expression and molecular pathway activation patterns in three normal blood, seven pediatric ALL and seven pediatric AML bone marrow samples. We identified 172/94 and 148/31 characteristic gene expression/pathway activation signatures, clearly distinguishing pediatric ALL and AML cells, respectively, from the normal blood. The pediatric AML and ALL cells differed by 139/34 gene expression/pathway activation biomarkers. For the adult 30 AML and 17 normal blood samples, we found 132/33 gene expression/pathway AML-specific features, of which only 7/2 were common for the adult and pediatric AML and, therefore, age-independent. At the pathway level, we found more differences than similarities between the adult and pediatric forms. These findings suggest that the adult and pediatric AMLs may require different treatment strategies.

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Section: Resultsmentioning

confidence: 99%

Molecular pathway activation features of pediatric acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) cells

Petrov

Suntsova

Mutorova

et al. 2016

Aging

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“…Here we unveil an additional mechanism supporting mitochondrial high OxPHOS activity in reponse to AraC treatment through the enhancement Previous studies have reported the pleiotropic roles of cAMP signaling and its major downstream effector PKA in different cancers including AML. Perez and colleagues showed that cAMP efflux from the cytoplasm protects AML cells from apoptosis (52). Similarly, others reported cAMP mediated protection of acute promyelocytic leukemia against anthracycline (53) or against arsenic trioxide-induced apoptosis (54).…”

Section: Discussionmentioning

confidence: 96%

Extracellular ATP and CD39 activate cAMP-mediated mitochondrial stress response to promote cytarabine resistance in acute myeloid leukemia

Aroua

Ghisi

Boet

et al. 2019

Preprint

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Relapses driven by chemoresistant leukemic cell populations are the main cause of mortality for patients with acute myeloid leukemia (AML). Here, we show that the ectonucleotidase CD39 (ENTPD1) is upregulated in cytarabine (AraC)-resistant leukemic cells from both AML cell lines and patient samples in vivo and in vitro. CD39 cell surface expression and activity is increased in AML patients upon chemotherapy compared to diagnosis and enrichment in CD39-expressing blasts is a marker of adverse prognosis in the clinics. High CD39 activity promotes AraC resistance by enhancing mitochondrial activity and biogenesis through activation of a cAMP-mediated response. Finally, genetic and pharmacological inhibition of CD39 eATPase activity blocks the mitochondrial reprogramming triggered by AraC treatment and markedly enhances its cytotoxicity in AML cells in vitro and in vivo. Together, these results reveal CD39 as a new prognostic marker and a promising therapeutic target to improve chemotherapy response in AML. SIGNIFICANCE: Extracellular ATP and CD39-cAMP-OxPHOS axis are key regulators of cytarabine resistance, offering a new promising therapeutic strategy in AML. * *

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“…Integrin Cytoplasmic domain-Associated Protein-1 (ICAP-1), a specific adaptor of the β1 integrin subunit cytoplasmic domain, was described as a negative regulator of adhesion in this study. In another study, the elevation of cytoplasmic cyclic nucleotides was suggested as another main mechanism of decreasing VLA-4 activation [63]. It will be interesting to elucidate the association of these individual components.…”

Section: Methodsmentioning

confidence: 95%

VLA-4 Expression and Activation in B Cell Malignancies: Functional and Clinical Aspects

Härzschel

Zucchetto

Gattei

et al. 2020

IJMS

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Lineage commitment and differentiation of hematopoietic cells takes place in well-defined microenvironmental surroundings. Communication with other cell types is a vital prerequisite for the normal functions of the immune system, while disturbances in this communication support the development and progression of neoplastic disease. Integrins such as the integrin very late antigen-4 (VLA-4; CD49d/CD29) control the localization of healthy as well as malignant B cells within the tissue, and thus determine the patterns of organ infiltration. Malignant B cells retain some key characteristics of their normal counterparts, with B cell receptor (BCR) signaling and integrin-mediated adhesion being essential mediators of tumor cell homing, survival and proliferation. It is thus not surprising that targeting the BCR pathway using small molecule inhibitors has proved highly effective in the treatment of B cell malignancies. Attenuation of BCR-dependent lymphoma–microenvironment interactions was, in this regard, described as a main mechanism critically contributing to the efficacy of these agents. Here, we review the contribution of VLA-4 to normal B cell differentiation on the one hand, and to the pathophysiology of B cell malignancies on the other hand. We describe its impact as a prognostic marker, its interplay with BCR signaling and its predictive role for novel BCR-targeting therapies, in chronic lymphocytic leukemia and beyond.

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Cyclic AMP efflux inhibitors as potential therapeutic agents for leukemia

Cited by 20 publications

References 130 publications

Molecular pathway activation features of pediatric acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) cells

Molecular pathway activation features of pediatric acute myeloid leukemia (AML) and acute lymphoblast leukemia (ALL) cells

Extracellular ATP and CD39 activate cAMP-mediated mitochondrial stress response to promote cytarabine resistance in acute myeloid leukemia

VLA-4 Expression and Activation in B Cell Malignancies: Functional and Clinical Aspects

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