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

Papa, Verónica; Tazzari, Pier Luigi; Chiarini, Francesca; Cappellini, Alessandra; Ricci, Francesca; Billi, Anna Maria; Evangelisti, Camilla; Ottaviani, Emanuela; Martinelli, Giovanni; Testoni, Nicoletta; McCubrey, James A.; Martelli, Alberto M.

doi:10.1038/sj.leu.2404980

Cited by 102 publications

(94 citation statements)

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“…15,34 This is consistent with our recent results, which showed no cytotoxic effect of perifosine in CD34 þ hematopoietic precursors from healthy donors. 22 Here, we have addressed perifosine efficacy in decreasing cell survival of PTEN-negative CEM T-ALL cells, including a subclone, which overexpresses P-gp. Perifosine, in a dose-dependent manner, decreased survival of both CEM-R and CEM-S cells.…”

Section: Discussionmentioning

confidence: 99%

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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

et al. 2008

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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)/Aktsignaling 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 NH 2 -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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Section: Discussionmentioning

confidence: 99%

“…22 Quantitation of blots by scanning was performed as previously reported. 23 Perifosine toxicity in P-gp-expressing CEM cells F Chiarini et al…”

Section: Western Blotting Analysismentioning

confidence: 99%

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

et al. 2008

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“…Because constitutive activation of AKT is the most common pathway abnormality in AML, dual PI3K/mTOR inhibitors (PI-103, BEZ235), mTORC1/2 inhibitors (OSI-027, PP242), and AKT inhibitors (perifosine) have been investigated in preclinical models and, at least in vitro, appear to be more effective than rapalogs. [183][184][185][186][187] Based on these results, early-phase clinical trials are ongoing in adults.…”

Section: Acute and Chronic Myelogenous Leukemiamentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen.Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual-and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignanc...

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“…5, 7), it caused a significant growth delay of both tumor models. Perifosine has been reported to induce apoptosis in several tumor cell lines, such as human lung cancer cells [13], human multiple myeloma cells [15,47], acute myelogenous leukemia cells [48] and Hodgkin Lymphoma cells [49]. As regard to tumor cell lines used in this work, perifosine significantly increased tumor cell death both in vitro and in vivo (Online resource 1, Fig.…”

Section: Perifosine Induces In Vivo Dr5 Expression On Tecsmentioning

confidence: 71%

“…In addition to targeting Akt and modulating JNK activation and DR5 expression, perifosine possesses other biologic activities (reviewed in [59]) that may contribute to the effects observed in this work. These include, accumulation into lipid rafts of the plasma membrane [60] and downregulation of ERK 1/2 phosphorylation [48]. Analysis of tumor xenografts revealed a strong reduction in ERK phosphorylation levels following perifosine treatment (data not shown), indicating that inhibition of MAPK signaling by perifosine toghether with Akt inhibition might also be involved in inducing tumor cells apoptosis and tumor growth delay.…”

Section: Discussionmentioning

confidence: 97%

Induction of death receptor 5 expression in tumor vasculature by perifosine restores the vascular disruption activity of TRAIL-expressing CD34+ cells

et al. 2013

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The proapoptotic death receptor 5 (DR5) expressed by tumor associated endothelial cells (TECs) mediates vascular disrupting effects of human CD34 ? cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (CD34-TRAIL 1 cells) in mice. Indeed, lack of DR5 on TECs causes resistance to CD34-TRAIL 1 cells. By xenografting in nonobese diabetic/severe combined immunodeficient mice the TRAIL-resistant lymphoma cell line SU-DHL-4V, which generates tumors lacking endothelial DR5 expression, here we demonstrate for the first time that the Akt inhibitor perifosine induces in vivo DR5 expression on TECs, thereby overcoming tumor resistance to the vascular disruption activity of CD34-TRAIL 1 cells. In fact, CD34-TRAIL 1 cells combined with perifosine, but not CD34-TRAIL 1 cells alone, exerted marked antivascular effects and caused a threefold increase of hemorrhagic necrosis in SU-DHL-4V tumors. Consistent with lack of DR5 expression, CD34-TRAIL 1 cells failed to affect the growth of SU-DHL-4V tumors, but CD34-TRAIL 1 cells plus perifosine reduced tumor volumes by 60 % compared with controls. In view of future clinical studies using membrane-bound TRAIL, our results highlight a strategy to rescue patients with primary or acquired resistance due to the lack of DR5 expression in tumor vasculature.

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

Cited by 102 publications

References 60 publications

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

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

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

Induction of death receptor 5 expression in tumor vasculature by perifosine restores the vascular disruption activity of TRAIL-expressing CD34+ cells

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