Selective small molecule inhibitors of p110α and δ isoforms of phosphoinosityl-3-kinase are cytotoxic to human acute myeloid leukemia progenitors

The phosphoinosityl-3-kinase (PI3K) pathway is frequently constitutively active in blast cells from acute myeloid leukemia (AML) patients. RNA and protein from all four catalytic isoforms of PI3K (p110 alpha, beta, gamma, and delta) were expressed in 38 AML samples, which also showed expression of phosphorylated Akt Ser473, indicating PI3K activation. Initial treatment of 12 AML samples with inhibitors targeting each of the four isoforms demonstrated that p110 alpha and delta inhibition are more effective in killing AML blast colony-forming cells (CFC) than p110 beta or gamma inhibition. In subsequent experiments, AML CFC from 46 patient samples were treated with the p110 alpha and delta selective inhibitors, the PI3K alpha inhibitor 2 or PCN5603, and dose-dependent progenitor kill and inhibition of phosphorylated Akt Ser473 expression was observed. AML samples were more sensitive to PI3K alpha inhibitor 2 and PCN5603 killing than normal bone marrow or normal peripheral blood CFC (median IC50 for AML and normal CFCs treated with PI3K alpha inhibitor 2, 1.8 and 4.3 mu M, respectively, and for PCN5603, 1.9 and 6.2 mu M, respectively). Furthermore, treatment of AML cells with PCN5603 also decreased survival of more primitive leukemia progenitors identified in long-term culture (AML long-term culture initiating cells),, while less toxicity toward normal bone marrow long-term culture initiating cells was observed. Selective inhibition of the p110 alpha and delta isoforms of PI3K kills AML progenitors while causing relative sparing of analogous normal cells. Crown Copyright (C) 2012 Published, by Elsevier Inc. on behalf of ISEH - Society for Hematology and Stem Cells. All rights reserved.