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(+) 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.

• Authors: V Papa, P L Tazzari, F Chiarini, A Cappellini, F Ricci, A M Billi, C Evangelisti, E Ottaviani, G Martinelli, N Testoni, J A McCubrey, A M Martelli
• Journal: Leukemia (Leukemia) Vol. 22 Issue 1 Pg. 147-60 (Jan 2008) ISSN: 1476-5551 [Electronic] England
• PMID: 17928881 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• BAD protein, human
• FASLG protein, human
• Fas Ligand Protein
• RNA, Messenger
• bcl-Associated Death Protein
• fas Receptor
• Phosphorylcholine
• perifosine
• Phosphatidylinositol 3-Kinases
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• MAP Kinase Kinase 4

Topics

• Apoptosis (drug effects)
• Blotting, Western
• Cell Proliferation (drug effects)
• Colony-Forming Units Assay
• Fas Ligand Protein (genetics, metabolism)
• Flow Cytometry
• Humans
• Immunoprecipitation
• Leukemia, Myeloid, Acute (drug therapy, metabolism)
• MAP Kinase Kinase 4 (metabolism)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation (drug effects)
• Phosphorylcholine (analogs & derivatives, pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• RNA, Messenger (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction
• Tumor Cells, Cultured
• bcl-Associated Death Protein (metabolism)
• fas Receptor (metabolism)
• fms-Like Tyrosine Kinase 3 (metabolism)