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Molecular Targets for Therapy

The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism

Leukemia volume 22, pages 1106–1116 (2008)Cite this article

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.

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Acknowledgements

This work was supported by grants from Fondazione CARISBO, Progetti Strategici Università di Bologna EF 2006. JAM was supported in part by Grant RO1CA090125 from the US National Cancer Institute (NCI/ NIH).

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Authors and Affiliations

  1. Dipartimento di Scienze Anatomiche Umane e Fisiopatologia dell'Apparato Locomotore, Università, di Bologna, Bologna, Italy

    F Chiarini, M Del Sole, S Mongiorgi, G C Gaboardi, I Mantovani, M Y Follo & A M Martelli

  2. Dipartimento di Scienze Motorie e della Salute, Università di Cassino, Cassino, Italy

    A Cappellini

  3. Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA

    J A McCubrey

  4. IGM-CNR, Sezione di Bologna c/o I.O.R., Bologna, Italy

    A M Martelli

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  1. F Chiarini
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Correspondence to A M Martelli.

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Chiarini, F., Del Sole, M., Mongiorgi, S. et al. The novel Akt inhibitor, perifosine, induces caspase-dependent apoptosis and downregulates P-glycoprotein expression in multidrug-resistant human T-acute leukemia cells by a JNK-dependent mechanism. Leukemia 22, 1106–1116 (2008). https://doi.org/10.1038/leu.2008.79

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