1. ¹Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Università di Bologna, Bologna, Italy
2. ²Servizio di Immunoematologia e Trasfusionale, Policlinico S Orsola-Malpighi, Bologna, Italy
3. ³Dipartimento di Scienze Motorie e della Salute, Università di Cassino, Cassino, Italy
4. ⁴Istituto di Ematologia ed Oncologia Medica Seràgnoli, Università di Bologna, Bologna, Italy
5. ⁵Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
6. ⁶IGM-CNR, Sezione di Bologna c/o IOR, Bologna, Italy

Correspondence: Professor AM Martelli, Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Sezione di Anatomia Umana, Cell Signalling Laboratory, Università di Bologna, Bologna 40126, Italy. E-mail: alberto.martelli@unibo.it or amartell@biocfarm.unibo.it

Received 21 June 2007; Revised 6 September 2007; Accepted 6 September 2007; Published online 11 October 2007.

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.