The Akt inhibitor,
perifosine, is an alkylphospholipid exhibiting antitumor properties and is currently in phase II clinical trials for various types of
cancer. The mechanisms by which
perifosine exerts its antitumor effects, including the induction of apoptosis, are not well understood. The current study focused on the effects of
perifosine on the induction of apoptosis and its underlying mechanisms in human
non-small cell lung cancer (NSCLC) cells.
Perifosine, at clinically achievable concentration ranges of 10 to 15 micromol/L, effectively inhibited the growth and induced apoptosis of NSCLC cells.
Perifosine inhibited Akt phosphorylation and reduced the levels of total Akt. Importantly, enforced activation of Akt attenuated
perifosine-induced apoptosis. These results indicate that Akt inhibition is necessary for
perifosine-induced apoptosis. Despite the activation of both
caspase-8 and
caspase-9,
perifosine strikingly induced the expression of the
tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL)
receptor, death receptor 5, and down-regulated cellular
FLICE-inhibitory protein (c-FLIP), an endogenous inhibitor of the extrinsic apoptotic pathway, with limited modulatory effects on the expression of other genes including Bcl-2, Bcl-X(L), PUMA, and
survivin. Silencing of either
caspase-8 or
death receptor 5 attenuated
perifosine-induced apoptosis. Consistently, further down-regulation of c-FLIP expression with c-FLIP
small interfering RNA sensitized cells to
perifosine-induced apoptosis, whereas enforced overexpression of ectopic c-FLIP conferred resistance to
perifosine. Collectively, these data indicate that activation of the extrinsic apoptotic pathway plays a critical role in
perifosine-induced apoptosis. Moreover,
perifosine cooperates with TRAIL to enhance the induction of apoptosis in human NSCLC cells, thus warranting future in vivo and clinical evaluation of
perifosine in combination with TRAIL in the treatment of NSCLC.