Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia

被引:290
作者
Martelli, A. M. [1 ]
Nyakern, M.
Tabellini, G.
Bortul, R.
Tazzari, P. L.
Evangelisti, C.
Cocco, L.
机构
[1] Univ Bologna, Dipartimento Sci Anat & Fisiopatol Apparato Locom, Sez Anat Umana, Cell Signalling Lab, I-40126 Bologna, Italy
[2] IOR, CNR, ITOI, Bologna, Italy
[3] Univ Brescia, Dipartimento Sci Biomed & Biotecnol, Sez Citol & Istol, Brescia, Italy
[4] Univ Trieste, Dipartimento Morfol Umana Normale, Trieste, Italy
[5] St Orsola Marcello Malpighi Hosp, Serv Immunoematol & Trasfus, Bologna, Italy
关键词
signal transduction networks; 3-phosphorylated inositol lipids; apoptosis; drug resistance; targeted molecular therapy;
D O I
10.1038/sj.leu.2404245
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is crucial to many aspects of cell growth, survival and apoptosis, and its constitutive activation has been implicated in the both the pathogenesis and the progression of a wide variety of neoplasias. Hence, this pathway is an attractive target for the development of novel anticancer strategies. Recent studies showed that PI3K/Akt signaling is frequently activated in acute myeloid leukemia (AML) patient blasts and strongly contributes to proliferation, survival and drug resistance of these cells. Upregulation of the PI3K/Akt network in AML may be due to several reasons, including FLT3, Ras or c-Kit mutations. Small molecules designed to selectively target key components of this signal transduction cascade induce apoptosis and/or markedly increase conventional drug sensitivity of AML blasts in vitro. Thus, inhibitory molecules are currently being developed for clinical use either as single agents or in combination with conventional therapies. However, the PI3K/Akt pathway is important for many physiological cellular functions and, in particular, for insulin signaling, so that its blockade in vivo might cause severe systemic side effects. In this review, we summarize the existing knowledge about PI3K/Akt signaling in AML cells and we examine the rationale for targeting this fundamental signal transduction network by means of selective pharmacological inhibitors.
引用
收藏
页码:911 / 928
页数:18
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