1. ¹Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Università, di Bologna, Bologna, Italy
2. ²Dipartimento di Scienze Motorie e della Salute, Università di Cassino, Cassino, Italy
3. ³Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
4. ⁴IGM-CNR, Sezione di Bologna c/o I.O.R., Bologna, Italy

Correspondence: Professor AM Martelli, Department of Anatomical Sciences, University of Bologna, Via Irnerio, 48, Bologna 40126, Italy. E-mail: alberto.martelli@.unibo.it

Received 18 February 2008; Revised 29 February 2008; Accepted 5 March 2008; Published online 3 April 2008.

Abstract

A significant impediment to the success of cancer chemotherapy is the occurrence of multidrug resistance, which, in many cases, is attributable to overexpression of membrane transport proteins, such as the 170-kDa P-glycoprotein (P-gp). Also, upregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt-signaling pathway is known to play an important role in drug resistance, and has been implicated in the aggressiveness of a number of different cancers, including T-acute lymphoblastic leukemia (T-ALL). We have investigated the therapeutic potential of the novel Akt inhibitor, perifosine (a synthetic alkylphospholipid), on human T-ALL CEM cells (CEM-R), characterized by both overexpression of P-gp and constitutive upregulation of the PI3K/Akt network. Perifosine treatment induced death by apoptosis in CEM-R cells. Apoptosis was characterized by caspase activation, Bid cleavage and cytochrome c release from mitochondria. The proapoptotic effect of perifosine was in part dependent on the Fas/FasL interactions and c-Jun NH₂-terminal kinase (JNK) activation, as well as on the integrity of lipid rafts. Perifosine downregulated the expression of P-gp mRNA and protein and this effect required JNK activity. Our findings indicate that perifosine is a promising therapeutic agent for treatment of T-ALL cases characterized by both upregulation of the PI3K/Akt survival pathway and overexpression of P-gp.