Liu TJ, Koul D, LaFortune T, Tiao N, Shen RJ, Maira SM, Garcia-Echevrria C, Yung WKNVP-BEZ235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas. Mol Cancer Ther 8: 2204-2210

Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Unit 431, 1515 Holcombe Boulevard, Houston, TX 77030. .
Molecular Cancer Therapeutics (Impact Factor: 5.68). 09/2009; 8(8):2204-10. DOI: 10.1158/1535-7163.MCT-09-0160
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Aberrant genetic alternations in human gliomas, such as amplification of epidermal growth factor receptor, mutation and/or deletion of tumor suppressor gene PTEN, and mutations of PIK3CA, contribute to constitutive activation of the phosphatidylinositol 3-kinase (PI3K) pathway. We investigated the potential antitumor activity of NVP-BEZ235, which is a novel dual PI3K/mammalian target of rapamycin (mTOR) inhibitor in gliomas. The compound suppressed glioma cell proliferation with IC(50) values in the low nanomolar range by specifically inhibiting the activity of target proteins including Akt, S6K1, S6, and 4EBP1 in the PI3K/Akt/mTOR signaling pathway. NVP-BEZ235 treatment of glioma cell lines led to G(1) cell cycle arrest and induced autophagy. Furthermore, expression of the vascular endothelial growth factor (VEGF), which is an important angiogenic modulator in glioma cells, was significantly decreased, suggesting that NVP-BEZ235 may also exert an antiangiogenic effect. Preclinical testing of the therapeutic efficacy of NVP-BEZ235 showed that it significantly prolonged the survival of tumor-bearing animals without causing any obvious toxicity. Tumor extracts harvested from animals after treatment showed that the compound inhibited the activity of target proteins in the PI3K/Akt/mTOR cascade. Immunohistochemical analyses also showed a significant reduction in staining for VEGF von Willebrand factor (factor VIII) in NVP-BEZ235-treated tumor sections compared with controls, further confirming that NVP-BEZ235 has an antiangiogenic effect in vivo. We conclude from these findings that NVP-BEZ235 antagonizes PI3K and mTOR signaling and induces cell cycle arrest, down-regulation of VEGF, and autophagy. These results warrant further development of NVP-BEZ235 for clinical trials for human gliomas or other advanced cancers with altered PI3K/Akt/mTOR signaling.

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Available from: Sauveur-Michel Maira, Oct 14, 2014
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    • "Its inhibition, currently being proved, increased radiosensitivity of some human cell lines, including SQ20B head and neck carcinoma cells and U251 glioblastoma cells [44]. Radiation sensitivity effect of NVP-BEZ235, a dual PI3K/mTOR inhibitor, reveals enhancement of apoptosis in human glioma cells, as well as cell cycle arrest, resulting in striking tumor radiosensitization, which extended the survival of brain tumor-bearing mice [45] [46] [47]. Likewise, NVP-BEZ235 prominently improved the radiosensitivity of PC-3 prostate cancer cells through inducing a G 2 /M arrest and enhanced proapoptotic effect after combined IR [48]. "
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    ABSTRACT: Much has been investigated to improve the beneficial effects of radiotherapy especially in that case where radioresistant behavior is observed. Beyond simple identification of resistant phenotype the discovery and development of specific molecular targets have demonstrated therapeutic potential in cancer treatment including radiotherapy. Alterations on transduction signaling pathway related with MAPK cascade are the main axis in cancer cellular proliferation even as cell migration and invasiveness in irradiated tumor cell lines; then, for that reason, more studies are in course focusing on, among others, DNA damage enhancement, apoptosis stimulation, and growth factors receptor blockages, showing promising in vitro results highlighting molecular targets associated with ionizing radiation as a new radiotherapy strategy to improve clinical outcome. In this review we discuss some of the main molecular targets related with tumor cell proliferation and migration as well as their potential contributions to radiation oncology improvements.
    BioMed Research International 09/2014; 2014:461687. DOI:10.1155/2014/461687 · 2.71 Impact Factor
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    • "Recently, several new classes of drugs targeting the PI3K/Akt/mTOR pathway have been developed to combat the problems of earlier agents, including unfavorable pharmacokinetics, toxicity, and poor selectivity [18]. NVP-BEZ-235 is a synthetic imidazo[4,5-c]quinoline derivative compound that acts as a selective dual pan-class I PI3K and mTOR kinase inhibitor [19], and reversibly binds the ATP-binding sites of class I PI3K and mTOR kinase, inhibiting their catalytic activities; it has been shown to inhibit PI3K/Akt/mTOR signaling and has anti-proliferative and anti-tumor activity in several cancers, including breast cancer [20], glioma [21], lymphoma [22], NSCLC [23], pancreatic cancer [24], and renal cell carcinoma [25]. In this study, we investigate the role of the PI3K/Akt/mTOR signaling pathway inhibition via BEZ-235 in the radiosensitization of a cisplatin-resistant (CDDP-R) NSCLC cell line. "
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    ABSTRACT: Introduction: Most drug resistant cancer cells also develop resistance to radiation therapy. In this study, we hypothesized that the dual inhibitor of phosphatidylinositol-3 kinase/mammalian target of rapamycin, NVP-BEZ-235, could potentially enhance radiosensitization in cisplatin-resistance (CDDP-R) non-small cell lung cancer (NSCLC) cells by disabling autophagy as a mechanism of self-preservation. Methods: We used both in vitro and in vivo approaches, including clonogenic assays, Western blotting, molecular analyses of autophagy and apoptosis, a xenograft model of tumor growth, and immunohistochemical analysis. Results: Basal p-Akt, p-mTOR and p-S6R proteins were enhanced in CDDP-R NSCLC cells. CDDP-R-resistant NSCLC cells are less radiation sensitive in comparison to parental cells (DER=0.82, p=0.02); BEZ-235 enhanced the radiosensitivity (DER=1.2, p=0.01). In addition, combining BEZ-235/RT showed a dramatic tumor growth delay in a mouse xenograft model. Immunohistochemistry showed that combination therapy yielded 50% decrease in caspase-3 activity. Moreover, cell proliferation was reduced by 87.8% and vascular density by 86.1%. These results were associated with a downregulation of PI3K/mTOR signaling pathway and an increase in autophagy. Conclusions: These findings may be utilized as a novel strategy to enhance the efficacy of radiation therapy in drug-selected non-small cell lung cancer exhibiting radioresistance.
    Genes & cancer 07/2014; 5(7-8):293-302.
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    • "Therefore, the search for further determinants of resistance may enable a better selection of patients potentially responsive to anti- EGFR drugs and the development of novel therapeutic strategies to overcome EGFR resistance. The mammalian target of rapamycin (mTOR) and the phosphoinositide 3-kinase (PI3K) signalling pathways have been found to have an important role in the pathogenesis of HNSCC (Liu et al, 2009), and data from literature suggest that PI3K antagonists are active against head and neck cancer cells (Bancroft et al, 2002). In HNSCC cell lines and tumour specimens, sensitivity to anti-EGFR therapy has been correlated with activation of phosphorylated Akt (Pernas et al, 2009). "
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    ABSTRACT: Background: Cetuximab is the only targeted agent approved for the treatment of head and neck squamous cell carcinomas (HNSCC), but low response rates and disease progression are frequently reported. As the phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathways have an important role in the pathogenesis of HNSCC, we investigated their involvement in cetuximab resistance. Methods: Different human squamous cancer cell lines sensitive or resistant to cetuximab were tested for the dual PI3K/mTOR inhibitor PF-05212384 (PKI-587), alone and in combination, both in vitro and in vivo. Results: Treatment with PKI-587 enhances sensitivity to cetuximab in vitro, even in the condition of epidermal growth factor receptor (EGFR) resistance. The combination of the two drugs inhibits cells survival, impairs the activation of signalling pathways and induces apoptosis. Interestingly, although significant inhibition of proliferation is observed in all cell lines treated with PKI-587 in combination with cetuximab, activation of apoptosis is evident in sensitive but not in resistant cell lines, in which autophagy is pre-eminent. In nude mice xenografted with resistant Kyse30 cells, the combined treatment significantly reduces tumour growth and prolongs mice survival. Conclusions: Phosphoinositide 3-kinase/mammalian target of rapamycin inhibition has an important role in the rescue of cetuximab resistance. Different mechanisms of cell death are induced by combined treatment depending on basal anti-EGFR responsiveness.
    British Journal of Cancer 05/2014; 110(12). DOI:10.1038/bjc.2014.241 · 4.84 Impact Factor
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