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Synergistic Proapoptotic Activity of Recombinant TRAIL Plus the Akt Inhibitor Perifosine in Acute Myelogenous Leukemia Cells

¹ Servizio di Immunoematologia e Trasfusionale, Policlinico S. Orsola-Malpighi, ² Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore and ³ Dipartimento di Ematologia ed Oncologia Medica "L. and A. Seràgnoli", Università di Bologna, ⁴ Istituto di Genetica Molecolare del Consiglio Nazionale delle Ricerche, Sezione di Bologna c/o Istituti Ortopedici Rizzoli, Bologna, Italy; ⁵ Dipartimento di Scienze Biomediche e Biotecnologie, Sezione di Istologia, Università di Brescia, Brescia, Italy; ⁶ Dipartimento Clinico di Biomedicina, Università di Trieste, Trieste, Italy; and ⁷ Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina

Requests for reprints: Alberto M. Martelli, Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Sezione di Anatomia Umana, Cell Signalling Laboratory, Università di Bologna, 40126 Bologna, Italy. Phone: 39-51209-1580; Fax: 39-51209-1695; E-mail: alberto.martelli{at}unibo.it.

Key Words: Akt signaling • apoptosis • caspase-8 • TRAIL • combination therapy

To potentiate the response of acute myelogenous leukemia (AML) cells to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) cytotoxicity, we have examined the efficacy of a combination with perifosine, a novel phosphatidylinositol-3-kinase (PI3K)/Akt signaling inhibitor. The rationale for using such a combination is that perifosine was recently described to increase TRAIL-R2 receptor expression and decrease the cellular FLICE-inhibitory protein (cFLIP) in human lung cancer cell lines. Perifosine and TRAIL both induced cell death by apoptosis in the THP-1 AML cell line, which is characterized by constitutive PI3K/Akt activation, but lacks functional p53. Perifosine, at concentrations below IC₅₀, dephosphorylated Akt and increased TRAIL-R2 levels, as shown by Western blot, reverse transcription-PCR, and flow cytometric analysis. Perifosine also decreased the long isoform of cFLIP (cFLIP-L) and the X-linked inhibitor of apoptosis protein (XIAP) expression. Perifosine and TRAIL synergized to activate caspase-8 and induce apoptosis, which was blocked by a caspase-8–selective inhibitor. Up-regulation of TRAIL-R2 expression was dependent on a protein kinase C/c-Jun-NH₂-kinase 2/c-Jun signaling pathway activated by perifosine through reactive oxygen species production. Perifosine also synergized with TRAIL in primary AML cells displaying constitutive activation of the Akt pathway by inducing apoptosis, Akt dephosphorylation, TRAIL-R2 up-regulation, cFLIP-L and XIAP down-regulation, and c-Jun phosphorylation. The combined treatment negatively affected the clonogenic activity of CD34⁺ cells from patients with AML. In contrast, CD34⁺ cells from healthy donors were resistant to perifosine and TRAIL treatment. Our findings suggest that the combination of perifosine and TRAIL might offer a novel therapeutic strategy for AML. [Cancer Res 2008;68(22):9394–403]

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