Proapoptotic activity and chemosensitizing effect of the novel Akt inhibitor perifosine in acute myelogenous leukemia cells

Abstract

The serine/threonine kinase Akt, a downstream effector of phosphatidylinositol 3-kinase (PI3K), is known to play an important role in antiapoptotic signaling and has been implicated in the aggressiveness of a number of different human cancers including acute myelogenous leukemia (AML). We have investigated the therapeutic potential of the novel Akt inhibitor, perifosine, on human AML cells. Perifosine is a synthetic alkylphospholipid, a new class of antitumor agents, which target plasma membrane and inhibit signal transduction networks. Perifosine was tested on THP-1 and MV 4-11 cell lines, as well as primary leukemia cells. Perifosine treatment induced cell death by apoptosis in AML cell lines. Perifosine caused Akt and ERK 1/2 dephosphorylation as well as caspase activation. In THP-1 cells, the proapoptotic effect of perifosine was partly dependent on the Fas/FasL system and c-jun-N-kinase activation. In MV 4-11 cells, perifosine downregulated phosphorylated Akt, but not phosphorylated FLT3. Moreover, perifosine reduced the clonogenic activity of AML, but not normal, CD34 þ cells, and markedly increased blast cell sensitivity to etoposide. Our findings indicate that perifosine, either alone or in combination with existing drugs, might be a promising therapeutic agent for the treatment of those AML cases characterized by upregulation of the PI3K-Akt survival pathway.

The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism

“…15,34 This is consistent with our recent results, which showed no cytotoxic effect of perifosine in CD34 þ hematopoietic precursors from healthy donors. 22 Here, we have addressed perifosine efficacy in decreasing cell survival of PTEN-negative CEM T-ALL cells, including a subclone, which overexpresses P-gp. Perifosine, in a dose-dependent manner, decreased survival of both CEM-R and CEM-S cells.…”

“…22 Quantitation of blots by scanning was performed as previously reported. 23 Perifosine toxicity in P-gp-expressing CEM cells F Chiarini et al…”

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

“…Because constitutive activation of AKT is the most common pathway abnormality in AML, dual PI3K/mTOR inhibitors (PI-103, BEZ235), mTORC1/2 inhibitors (OSI-027, PP242), and AKT inhibitors (perifosine) have been investigated in preclinical models and, at least in vitro, appear to be more effective than rapalogs. [183][184][185][186][187] Based on these results, early-phase clinical trials are ongoing in adults.…”

Induction of death receptor 5 expression in tumor vasculature by perifosine restores the vascular disruption activity of TRAIL-expressing CD34+ cells

“…5, 7), it caused a significant growth delay of both tumor models. Perifosine has been reported to induce apoptosis in several tumor cell lines, such as human lung cancer cells [13], human multiple myeloma cells [15,47], acute myelogenous leukemia cells [48] and Hodgkin Lymphoma cells [49]. As regard to tumor cell lines used in this work, perifosine significantly increased tumor cell death both in vitro and in vivo (Online resource 1, Fig.…”

“…In addition to targeting Akt and modulating JNK activation and DR5 expression, perifosine possesses other biologic activities (reviewed in [59]) that may contribute to the effects observed in this work. These include, accumulation into lipid rafts of the plasma membrane [60] and downregulation of ERK 1/2 phosphorylation [48]. Analysis of tumor xenografts revealed a strong reduction in ERK phosphorylation levels following perifosine treatment (data not shown), indicating that inhibition of MAPK signaling by perifosine toghether with Akt inhibition might also be involved in inducing tumor cells apoptosis and tumor growth delay.…”