Phosphatidylinositol 3-kinase inhibition potentiates glucocorticoid response in B-cell acute lymphoblastic leukemia

Autor: Rita Fragoso, Franco Locatelli, Alessandra Cappellini, Francesca Buontempo, Annalisa Lonetti, Mariana L. Oliveira, João Pedro Taborda Barata, Luca M. Neri, Alberto M. Martelli, Andrea Pession, Alice Bertaina, Lucia Manzoli, Cecilia Evangelisti, Francesca Chiarini, Ester Orsini, Camilla Evangelisti, Carolina Simioni
Přispěvatelé: Evangelisti, Cecilia, Cappellini, Alessandra, Oliveira, Mariana, Fragoso, Rita, Barata, João T., Bertaina, Alice, Locatelli, Franco, Simioni, Carolina, Neri, Luca M., Chiarini, Francesca, Lonetti, Annalisa, Buontempo, Francesca, Orsini, Ester, Pession, Andrea, Manzoli, Lucia, Martelli, Alberto Maria, Evangelisti, Camilla
Rok vydání: 2017
Předmět:
0301 basic medicine
Cell cycle checkpoint
Physiology
Clinical Biochemistry
Apoptosis
ALL
dexamethasone
PI3K inhibitors
targeted therapy
Pharmacology
Dexamethasone
Antineoplastic Agent
chemistry.chemical_compound
0302 clinical medicine
Glucocorticoid
Cell Movement
Cytotoxic T cell
Medicine
Receptor
Child
Class I Phosphatidylinositol 3-Kinase
B-Lymphocytes
Triazines
B-Lymphocyte
Thiazolidinedione
Precursor Cell Lymphoblastic Leukemia-Lymphoma
3. Good health
Triazine
Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA
030220 oncology & carcinogenesis
Child
Preschool
Signal transduction
Heterocyclic Compounds
3-Ring
Human
Quinoxaline
Class I Phosphatidylinositol 3-Kinases
Antineoplastic Agents
PI3K inhibitor
Quinazolinone
NO
03 medical and health sciences
Cell Cycle Checkpoint
Cell Line
Tumor
Quinoxalines
Humans
Phosphatidylinositol
Protein kinase B
Purine
Glucocorticoids
PI3K/AKT/mTOR pathway
Quinazolinones
Isoquinoline
business.industry
Apoptosi
Cell Biology
Cell Cycle Checkpoints
Isoquinolines
030104 developmental biology
chemistry
Purines
Thiazolidinediones
business
Proto-Oncogene Proteins c-akt
Zdroj: Journal of Cellular Physiology
ISSN: 1097-4652
Popis: Despite remarkable progress in polychemotherapy protocols, pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains fatal in around 20% of cases. Hence, novel targeted therapies are needed for patients with poor prognosis. Glucocorticoids (GCs) are drugs commonly administrated for B-ALL treatment. Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling pathway is frequently observed in B-ALL and contributes to GC-resistance. Here, we analyzed for the first time to our knowledge, the therapeutic potential of pan and isoform-selective PI3K p110 inhibitors, alone or combined with dexamethasone (DEX), in B-ALL leukemia cell lines and patient samples. We found that a pan PI3K p110 inhibitor displayed the most powerful cytotoxic effects in B-ALL cells, by inducing cell cycle arrest and apoptosis. Both a pan PI3K p110 inhibitor and a dual γ/δ PI3K p110 inhibitor sensitized B-ALL cells to DEX by restoring nuclear translocation of the GC receptor and counteracted stroma-induced DEX-resistance. Finally, gene expression analysis documented that, on one hand the combination consisting of a pan PI3K p110 inhibitor and DEX strengthened the DEX-induced up- or down-regulation of several genes involved in apoptosis, while on the other, it rescued the effects of genes that might be involved in GC-resistance. Overall, our findings strongly suggest that PI3K p110 inhibition could be a promising strategy for treating B-ALL patients by improving GC therapeutic effects and/or overcoming GC-resistance.
Databáze: OpenAIRE
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