The pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma cells for apoptosis by inhibiting DNA repair

Westhoff, Mike‐Andrew; Kandenwein, J. A.; Karl, Sabine; Vellanki, Sri HariKrishna; Braun, Veit; Eramo, Adriana; Antoniadis, Gregor; Debatin, Klaus‐Michael; Fulda, Simone

doi:10.1038/onc.2009.215

Cited by 70 publications

(59 citation statements)

References 50 publications

(75 reference statements)

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“…This result is in accordance with our recent study showing that phosphorylation of S6 ribosomal protein does not correlate with poor prognosis in neuroblastoma, whereas phosphorylation of Akt does correlate (13). In glioblastoma, we similarly found that mTOR inhibition does not enhance TRAILor doxorubicin-induced apoptosis (20,30). By comparison, mTOR inhibitors have been reported to suppress tumor growth and angiogenesis in neuroblastoma cells with MYCN amplification (31) and to induce apoptosis together with chemotherapeutic agents (20,32), implying a context-dependent role of mTOR signaling in neuroblastoma.…”

Section: Discussionsupporting

confidence: 93%

“…Therapeutic intervention of aberrant PI3K/Akt activation in cancers, including neuroblastoma, is currently an area of high interest. So far, PI103 is described as a chemosensitizer in combination with anticancer drugs, for example, in T-cell acute lymphoblastic leukemia (36), glioblastoma (30,37), or chronic lymphocytic leukemia (38). Our study identifies a novel indication for PI103 by showing that PI103 sensitizes for TRAIL-induced apoptosis.…”

Section: Discussionmentioning

confidence: 70%

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Targeting Aberrant PI3K/Akt Activation by PI103 Restores Sensitivity to TRAIL-Induced Apoptosis in Neuroblastoma

Opel

Naumann

Schneider

et al. 2011

Clinical Cancer Research

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Purpose: Because we recently identified Akt activation as a novel poor prognostic indicator in neuroblastoma, we investigated whether phosphoinositide 3 0 -kinase (PI3K) inhibition sensitizes neuroblastoma cells for TRAIL-induced apoptosis.Experimental Design: The effect of pharmacological or genetic inhibition of PI3K or mTOR was analyzed on apoptosis induction, clonogenic survival, and activation of apoptosis signaling pathways in vitro and in a neuroblastoma in vivo model. The functional relevance of individual Bcl-2 family proteins was examined by knockdown or overexpression experiments.Results: The PI3K inhibitor PI103 cooperates with TRAIL to synergistically induce apoptosis (combination index < 0

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 70%

Targeting Aberrant PI3K/Akt Activation by PI103 Restores Sensitivity to TRAIL-Induced Apoptosis in Neuroblastoma

Opel

Naumann

Schneider

et al. 2011

Clinical Cancer Research

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“…In this study, we report on the combination of PI-103 and mNSC-TRAIL in our glioma models and demonstrate the in vitro effects of PI-103 and S-TRAIL focusing on the viability and apoptosis of a panel of established glioma cell lines. Prior to our study, a few other studies reported the combination effect of PI-103 with EGFR inhibition (32), radiation (31), and chemotherapy-induced apoptosis (37). To our knowledge, this is the first study that examines the combined effect of PI-103 with TRAIL in glioma cells both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 91%

A Dual PI3K/mTOR Inhibitor, PI-103, Cooperates with Stem Cell–Delivered TRAIL in Experimental Glioma Models

et al. 2011

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The resistance of glioma cells to a number of antitumor agents and the highly invasive nature of glioma cells that escape the primary tumor mass are key impediments to the eradication of tumors in glioma patients. In this study, we evaluated the therapeutic efficacy of a novel PI3-kinase/mTOR inhibitor, PI-103, in established glioma lines and primary CD133 þ glioma-initiating cells and explored the potential of combining PI-103 with stem celldelivered secretable tumor necrosis factor apoptosis-inducing ligand (S-TRAIL) both in vitro and in orthotopic mouse models of gliomas. We show that PI-103 inhibits proliferation and invasion, causes G 0 -G 1 arrest in cell cycle, and results in significant attenuation of orthotopic tumor growth in vivo. Establishing cocultures of neural stem cells (NSC) and glioma cells, we show that PI-103 augments the response of glioma cells to stem celldelivered S-TRAIL. Using bimodal optical imaging, we show that when different regimens of systemic PI-103 delivery are combined with NSC-derived S-TRAIL, a significant reduction in tumor volumes is observed compared with PI-103 treatment alone. To our knowledge, this is the first study that reveals the antitumor effect of PI-103 in intracranial gliomas. Our findings offer a preclinical rationale for application of mechanismbased systemically delivered antiproliferative agents and novel stem cell-based proapoptotic therapies to improve treatment of malignant gliomas. Cancer Res; 71(1); 154-63. Ó2010 AACR.

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“…There are so far only few studies using PI3K inhibitors as chemosensitizers, for example in T-cell acute lymphoblastic leukemia (Chiarini et al, 2009), glioblastoma (Guillard et al, 2009;Westhoff et al, 2009) or chronic lymphocytic leukemia (Niedermeier et al, 2009), and little is yet known about the underlying molecular mechanisms of sensitization. Thus, the novelty of our study resides in particular in the elucidation of the molecular events mediating the cooperative cytotoxicity of the recently developed PI3K inhibitor PI103 and anticancer drugs, such as Doxorubicin, by demonstrating that chemosensitization by PI103 critically depends on mitochondrial outer membrane permeabilization as the result of a shift towards pro-apoptotic Bcl-2 proteins.…”

Section: Targeting Pi3k In Neuroblastomamentioning

confidence: 99%

PI3K inhibitors prime neuroblastoma cells for chemotherapy by shifting the balance towards pro-apoptotic Bcl-2 proteins and enhanced mitochondrial apoptosis

et al. 2010

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We recently identified activation of phosphatidylinositol 3 0 -kinase (PI3K)/Akt as a novel predictor of poor outcome in neuroblastoma. Here, we investigated the effect of smallmolecule PI3K inhibitors on chemosensitivity. We provide first evidence that PI3K inhibitors, for example PI103, synergize with various chemotherapeutics (Doxorubicin, Etoposide, Topotecan, Cisplatin, Vincristine and Taxol) to trigger apoptosis in neuroblastoma cells (combination index: high synergy). Mechanistic studies reveal that PI103 cooperates with Doxorubicin to reduce Mcl-1 expression and Bim EL phosphorylation and to upregulate Noxa and Bim EL levels. This shifted ratio of pro-and antiapoptotic Bcl-2 proteins results in increased Bax/Bak conformational change, loss of mitochondrial membrane potential, cytochrome c release, caspase activation and caspase-dependent apoptosis. Although Mcl-1 knockdown enhances Doxorubicin-and PI103-induced apoptosis, silencing of Noxa, Bax/ Bak or p53 reduces apoptosis, underscoring the functional relevance of the Doxorubicin-and PI103-mediated modulation of these proteins for chemosensitization. Bcl-2 overexpression inhibits Bax activation, mitochondrial perturbations, cleavage of caspases and Bid, and apoptosis, confirming the central role of the mitochondrial pathway for chemosensitization. Interestingly, the broad-range caspase inhibitor zVAD.fmk does not interfere with Bax activation or mitochondrial outer membrane permeabilization, whereas it blocks caspase activation and apoptosis, thus placing mitochondrial events upstream of caspase activation. Importantly, PI103 and Doxorubicin cooperate to induce apoptosis and to suppress tumor growth in patients' derived primary neuroblastoma cells and in an in vivo neuroblastoma model, underlining the clinical relevance of the results. Thus, targeting PI3K presents a novel and promising strategy to sensitize neuroblastoma cells for chemotherapy-induced apoptosis, which has important implications for the development of targeted therapies for neuroblastoma.

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The pyridinylfuranopyrimidine inhibitor, PI-103, chemosensitizes glioblastoma cells for apoptosis by inhibiting DNA repair

Cited by 70 publications

References 50 publications

Targeting Aberrant PI3K/Akt Activation by PI103 Restores Sensitivity to TRAIL-Induced Apoptosis in Neuroblastoma

Targeting Aberrant PI3K/Akt Activation by PI103 Restores Sensitivity to TRAIL-Induced Apoptosis in Neuroblastoma

A Dual PI3K/mTOR Inhibitor, PI-103, Cooperates with Stem Cell–Delivered TRAIL in Experimental Glioma Models

PI3K inhibitors prime neuroblastoma cells for chemotherapy by shifting the balance towards pro-apoptotic Bcl-2 proteins and enhanced mitochondrial apoptosis

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