Erucylphosphohomocholine, the first intravenously applicable alkylphosphocholine, is cytotoxic to acute myelogenous leukemia cells through JNK- and PP2A-dependent mechanisms

Martelli, Alberto M.; Papa, Verónica; Tazzari, Pier Luigi; Ricci, Francesca; Evangelisti, Camilla; Chiarini, Francesca; Grimaldi, Cecilia; Cappellini, Alessandra; Martinelli, Giovanni; Ottaviani, Emanuela; Pagliaro, Pasqualepaolo; Horn, Stefan; Bäsecke, Jörg; Lindner, Lars H.; Eibl, Hansjörg; McCubrey, James A.

doi:10.1038/leu.2010.32

Cited by 33 publications

(24 citation statements)

References 63 publications

(77 reference statements)

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“…Erufosine combined with etoposide and cytarabine acts additively in acute myeloid leukemia [142] . Erufosine causes cell death in acute myeloid leukemia by JNK 1/2 activation and ERK 1/2 dephosphorylation, leading to apoptosis [143] . Cytotoxic effects of Erufosine on chronic lymphocytic leukemia (CLL) and multiple myeloma have also been observed.…”

Section: Akt Inhibitorsmentioning

confidence: 99%

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

2012

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The PI3K-Akt pathway is a vital regulator of cell proliferation and survival. Alterations in the PIK3CA gene that lead to enhanced PI3K kinase activity have been reported in many human cancer types, including cancers of the colon, breast, brain, liver, stomach and lung. Deregulation of PI3K causes aberrant Akt activity. Therefore targeting this pathway could have implications for cancer treatment. The first generation PI3K-Akt inhibitors were proven to be highly effective with a low IC 50 , but later, they were shown to have toxic side effects and poor pharmacological properties and selectivity. Thus, these inhibitors were only effective in preclinical models. However, derivatives of these first generation inhibitors are much more selective and are quite effective in targeting the PI3K-Akt pathway, either alone or in combination. These second-generation inhibitors are essentially a specific chemical moiety that helps to form a strong hydrogen bond interaction with the PI3K/Akt molecule. The goal of this review is to delineate the current efforts that have been undertaken to inhibit the various components of the PI3K and Akt pathway in different types of cancer both in vitro and in vivo. Our focus here is on these novel therapies and their inhibitory effects that depend upon their chemical nature, as well as their development towards clinical trials.

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Section: Akt Inhibitorsmentioning

confidence: 99%

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

2012

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“…25 siRNA downregulation of Bcl-XL This was performed as previously described, 26 using Bcl-XL si-Genome duplexes D-003458-01-0010 and D-003458-04-0010 from Dharmacon (Chicago, IL, USA). Scrambled siCONTROL Nontargeting siRNA no.…”

Section: Western Blot Analysismentioning

confidence: 99%

Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

et al. 2012

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“…The Hoechst 33342 dye was excited at 366 nm. Side population (SP) cells were gated by the FL1/FL3 histogram, whereas ABC transporter staining was evaluated on the FL2 channel (27,28). …”

Section: Flow Cytometric Detection Of T-all Side Population Cellsmentioning

confidence: 99%

Activity of the Novel Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 against T-Cell Acute Lymphoblastic Leukemia

et al. 2010

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Recent findings have highlighted that constitutively active phosphatidylinositol 3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it upregulates cell proliferation, survival, and drug resistance. These observations lend compelling weight to the application of PI3K/Akt/mTOR inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of the novel dual PI3K/mTOR inhibitor NVP-BEZ235, an orally bioavailable imidazoquinoline derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. NVP-BEZ235 was cytotoxic to a panel of T-ALL cell lines as determined by MTT assays. NVP-BEZ235 treatment resulted in cell cycle arrest and apoptosis. Western blots showed a dose-and timedependent dephosphorylation of Akt and mTORC1 downstream targets in response to NVP-BEZ235. Remarkably, NVP-BEZ235 targeted the side population of both T-ALL cell lines and patient lymphoblasts, which might correspond to leukemia-initiating cells, and synergized with chemotherapeutic agents (cyclophosphamide, cytarabine, dexamethasone) currently used for treating T-ALL patients. NVP-BEZ235 reduced chemoresistance to vincristine induced in Jurkat cells by coculturing with MS-5 stromal cells, which mimic the bone marrow microenvironment. NVP-BEZ235 was cytotoxic to T-ALL patient lymphoblasts displaying pathway activation, where the drug dephosphorylated eukaryotic initiation factor 4E-binding protein 1, at variance with rapamycin. Taken together, our findings indicate that longitudinal inhibition at two nodes of the PI3K/Akt/mTOR network with NVP-BEZ235, either alone or in combination with chemotherapeutic drugs, may be an efficient treatment of those T-ALLs that have aberrant upregulation of this signaling pathway for their proliferation and survival.

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Erucylphosphohomocholine, the first intravenously applicable alkylphosphocholine, is cytotoxic to acute myelogenous leukemia cells through JNK- and PP2A-dependent mechanisms

Cited by 33 publications

References 63 publications

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

Activity of the Novel Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 against T-Cell Acute Lymphoblastic Leukemia

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