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

Leukemia. 2008 Jan;22(1):147-60. doi: 10.1038/sj.leu.2404980. Epub 2007 Oct 11.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis / drug effects*
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Colony-Forming Units Assay
  • Fas Ligand Protein / genetics
  • Fas Ligand Protein / metabolism
  • Flow Cytometry
  • Humans
  • Immunoprecipitation
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / 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*
  • Phosphorylcholine / pharmacology
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / 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


  • 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