A selective inhibitor of the p110δ isoform of PI 3-kinase inhibits AML cell proliferation and survival and increases the cytotoxic effects of VP16
A selective inhibitor of the p110δ isoform of PI 3-kinase inhibits AML cell proliferation and survival and increases the cytotoxic effects of VP16
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DOI：
10.1038/sj.onc.1209670
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发表时间：
2006-10-01
期刊：
影响因子：
8
通讯作者：
Khwaja, A.
中科院分区：
文献类型：
--
作者：
Billottet, C.;Grandage, V. L.;Khwaja, A.
目前急性髓性白血病（AML）的治疗是次优的，复发率高。有强有力的证据表明，组成型磷脂酰肌醇3-激酶（PI 3 K）活性在AML的病理生理学中起着重要作用。PI 3 K产物来源于许多PI 3 K催化亚型（I类、II类和III类）的活性，但这些酶在AML中的相对贡献仍未知。由于PI 3 K的非亚型选择性抑制剂如LY 294002可能对正常组织产生不必要的毒性，我们研究了白细胞限制性p110 δ PI 3 K亚型在14例AML中的作用。p110 d在所有病例中均被检测到，而其他I类PI 3 K的表达水平变化更广泛，并且通常检测不到。p110 δ-选择性化合物IC 87114抑制PI 3 K靶标Akt/PKB的组成性磷酸化，并将细胞数量减少至平均66 +/- 5%（范围14-88%）。在8例病例中，IC 87114和VP 16（拓扑异构酶II抑制剂）的组合在减少活细胞数方面具有协同作用，并且与组成型NF-κ B活性的降低相关。IC 87114对正常造血祖细胞的增殖和存活没有直接的副作用或增强VP 16的活性。总体而言，我们的研究结果确定了p110 d亚型作为AML的潜在治疗靶点，并支持使用亚型选择性广谱PI 3 K抑制剂的临床方法。
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 p110 delta PI3K isoform in 14 cases of AML. p110d was detected in all cases whereas the expression levels of the other class I PI3Ks varied more widely, and were often undetectable. The p110 delta-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-kappa B 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 p110d isoform as a potential therapeutic target in AML and support a clinical approach to use isoform-selective over broad-spectrum PI3K inhibitors.