The pan-class i phosphatidyl-inositol-3 kinase inhibitor NVP-BKM120 demonstrates anti-leukemic activity in acute myeloid leukemia

Matteo Allegretti, Maria Rosaria Ricciardi, Roberto Licchetta, Simone Mirabilii, Stefania Orecchioni, Francesca Reggiani, Giovanna Talarico, Roberto Foà, Francesco Bertolini, Sergio Amadori, Maria Rosaria Torrisi, Agostino Tafuri

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Abstract

Aberrant activation of the PI3K/Akt/mTOR pathway is a common feature of acute myeloid leukemia (AML) patients contributing to chemoresistance, disease progression and unfavourable outcome. Therefore, inhibition of this pathway may represent a potential therapeutic approach in AML. The aim of this study was to evaluate the pre-clinical activity of NVP-BKM120 (BKM120), a selective pan-class I PI3K inhibitor, on AML cell lines and primary samples. Our results demonstrate that BKM120 abrogates the activity of the PI3K/Akt/mTOR signaling, promoting cell growth arrest and significant apoptosis in a dose- and time-dependent manner in AML cells but not in the normal counterpart. BKM120-induced cytotoxicity is associated with a profound modulation of metabolic behaviour in both cell lines and primary samples. In addition, BKM120 synergizes with the glycolitic inhibitor dichloroacetate enhancing apoptosis induction at lower doses. Finally, in vivo administration of BKM120 to a xenotransplant mouse model of AML significantly inhibited leukemia progression and improved the overall survival of treated mice. Taken together, our findings indicate that BKM120, alone or in combination with other drugs, has a significant anti-leukemic activity supporting its clinical development as a novel therapeutic agent in AML.

Original languageEnglish
Article number18137
JournalScientific Reports
Volume5
DOIs
Publication statusPublished - Dec 17 2015

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Phosphatidylinositols
Acute Myeloid Leukemia
Phosphotransferases
Phosphatidylinositol 3-Kinases
Myeloid Cells
Apoptosis
Cell Line
NVP-BKM120
Disease Progression
Leukemia
Survival
Therapeutics
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • General

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The pan-class i phosphatidyl-inositol-3 kinase inhibitor NVP-BKM120 demonstrates anti-leukemic activity in acute myeloid leukemia. / Allegretti, Matteo; Ricciardi, Maria Rosaria; Licchetta, Roberto; Mirabilii, Simone; Orecchioni, Stefania; Reggiani, Francesca; Talarico, Giovanna; Foà, Roberto; Bertolini, Francesco; Amadori, Sergio; Torrisi, Maria Rosaria; Tafuri, Agostino.

In: Scientific Reports, Vol. 5, 18137, 17.12.2015.

Research output: Contribution to journalArticle

Allegretti, M, Ricciardi, MR, Licchetta, R, Mirabilii, S, Orecchioni, S, Reggiani, F, Talarico, G, Foà, R, Bertolini, F, Amadori, S, Torrisi, MR & Tafuri, A 2015, 'The pan-class i phosphatidyl-inositol-3 kinase inhibitor NVP-BKM120 demonstrates anti-leukemic activity in acute myeloid leukemia', Scientific Reports, vol. 5, 18137. https://doi.org/10.1038/srep18137
Allegretti, Matteo ; Ricciardi, Maria Rosaria ; Licchetta, Roberto ; Mirabilii, Simone ; Orecchioni, Stefania ; Reggiani, Francesca ; Talarico, Giovanna ; Foà, Roberto ; Bertolini, Francesco ; Amadori, Sergio ; Torrisi, Maria Rosaria ; Tafuri, Agostino. / The pan-class i phosphatidyl-inositol-3 kinase inhibitor NVP-BKM120 demonstrates anti-leukemic activity in acute myeloid leukemia. In: Scientific Reports. 2015 ; Vol. 5.
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