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

被引:32
作者
Allegretti, Matteo [1 ]
Ricciardi, Maria Rosaria [2 ]
Licchetta, Roberto [1 ]
Mirabilii, Simone [1 ]
Orecchioni, Stefania [3 ]
Reggiani, Francesca [3 ]
Talarico, Giovanna [3 ]
Foa, Roberto [1 ]
Bertolini, Francesco [3 ]
Amadori, Sergio [4 ]
Torrisi, Maria Rosaria [2 ]
Tafuri, Agostino [2 ]
机构
[1] Univ Roma La Sapienza, Dept Cellular Biotechnol & Hematol, I-00185 Rome, Italy
[2] Univ Roma La Sapienza, St Andrea Hosp, Dept Clin & Mol Med, I-00185 Rome, Italy
[3] European Inst Oncol, Div Clin Haematol Oncol, Milan, Italy
[4] Tor Vergata Univ Hosp, Dept Hematol, Rome, Italy
关键词
ANTITUMOR-ACTIVITY; CELL-DEATH; SIGNALING PATHWAYS; PI3K INHIBITION; CANCER; AKT; MTOR; PHOSPHORYLATION; COMBINATION; SURVIVAL;
D O I
10.1038/srep18137
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页数:11
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