Phosphatidylinositol 3-kinase inhibition potentiates glucocorticoid response in B-cell acute lymphoblastic leukemia.
Cecilia EvangelistiAlessandra CappelliniMariana OliveiraRita FragosoJoão T BarataAlice BertainaFranco LocatelliCarolina SimioniLuca M NeriFrancesca ChiariniAnnalisa LonettiFrancesca BuontempoEster OrsiniAndrea PessionLucia ManzoliAlberto Maria MartelliCamilla EvangelistiPublished in: Journal of cellular physiology (2017)
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.
Keyphrases
- cell cycle arrest
- pi k akt
- signaling pathway
- acute lymphoblastic leukemia
- cell death
- poor prognosis
- cell proliferation
- induced apoptosis
- gas chromatography
- protein kinase
- long non coding rna
- end stage renal disease
- high glucose
- healthcare
- epithelial mesenchymal transition
- acute myeloid leukemia
- diabetic rats
- allogeneic hematopoietic stem cell transplantation
- genome wide
- ejection fraction
- newly diagnosed
- chronic kidney disease
- genome wide identification
- endoplasmic reticulum stress
- bone marrow
- low dose
- prognostic factors
- mass spectrometry
- endothelial cells
- dna methylation
- young adults
- gene expression
- peritoneal dialysis
- transcription factor
- binding protein
- combination therapy
- smoking cessation
- replacement therapy
- solid phase extraction