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

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.