title: A selective inhibitor of the p110delta isoform of PI 3-kinase inhibits AML cell proliferation and survival and increases the cytotoxic effects of VP16.
abstract: Current therapy for acute myeloid leukaemia (AML) is suboptimal with a high incidence of relapse. There is strong evidence that constitutive phosphoinositide 3-kinase (PI3K) activity plays a significant role in the pathophysiology of AML. PI3K products are derived from the activity of a number of PI3K catalytic isoforms (class I, II and III) but the relative contribution of these enzymes in AML remains unknown. As non-isoform-selective inhibitors of PI3K such as LY294002 may produce unwanted toxicity to normal tissues, we have investigated the role of the leukocyte-restricted p110delta PI3K isoform in 14 cases of AML. p110delta was detected in all cases whereas the expression levels of the other class I PI3Ks varied more widely, and were often undetectable. The p110delta-selective compound IC87114 inhibited constitutive phosphorylation of the PI3K target Akt/PKB and reduced cell number to a mean of 66+/-5% (range 14-88%). In eight cases, the combination of IC87114 and VP16 (a topoisomerase II inhibitor) was synergistic in reducing viable cell number, and was associated with a reduction in constitutive NF-kappaB activity. IC87114 did not have direct adverse effects or enhance the activity of VP16 on the proliferation and survival of normal haemopoietic progenitors. Overall, our results identify the p110delta isoform as a potential therapeutic target in AML and support a clinical approach to use isoform-selective over broad-spectrum PI3K inhibitors.
authors.affiliation: Cell Signalling in Cancer, Ludwig Institute for Cancer Research, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Billottet
authors.forename: V L
authors.initials: VL
authors.lastname: Grandage
authors.forename: R E
authors.initials: RE
authors.lastname: Gale
authors.forename: A
authors.initials: A
authors.lastname: Quattropani
authors.forename: C
authors.initials: C
authors.lastname: Rommel
authors.forename: B
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.forename: A
authors.initials: A
authors.lastname: Khwaja
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D004357:Drug Synergism; D004789:Enzyme Activation; D005047:Etoposide / Q000627:therapeutic use*; D006801:Humans; D066298:In Vitro Techniques; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000225:Adenine; D058534:Class I Phosphatidylinositol 3-Kinases; D005047:Etoposide; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D011799:Quinazolines; C477872:IC 87114; C486018:PIK3CD protein, human