title: NVP-BEZ235, a novel dual PI3K-mTOR inhibitor displays anti-glioma activity and reduces chemoresistance to temozolomide in human glioma cells.
abstract: Glioblastoma multiforme (GBM) is the most frequent and most aggressive brain tumor in adults. The introduction of temozolomide (TMZ) has advanced chemotherapy for malignant gliomas. However, a considerable number of GBM cases are refractory to TMZ, the need for more effective therapeutic options is overwhelming. Mounting evidence shows that endogenous AKT (protein kinase B) activity can be activated in response to clinically relevant concentrations of TMZ. AKT activation correlated with the increased tumorigenicity, invasiveness and stemness and overexpression of an active form of AKT increases glioma cell resistance to TMZ. Previous studies also show that TMZ contributes to glioma cell apoptosis by inhibiting mTOR signaling. Thus, we hypothesized that the dual PI3K-mTOR inhibitor NVP-BEZ235 may act as antitumor agent against gliomas and potentiate the cytotoxicity of TMZ. In the present study, we found that NVP-BEZ235 treatment of glioma cell lines led to G1 cell cycle arrest, and induced apoptosis. Combination treatment with both TMZ and NVP-BEZ235 resulted in synergistically inhibited glioma cell growth and induced apoptosis (combination index CI<1) in a subset of glioma cell lines, as shown in the increased levels of Bax, and active Caspase-3, and decreased level of Bcl-2. Furthermore, NVP-BEZ235 treatment reversed p-AKT levels enhanced by TMZ. Inhibition of mTOR (p70S6K) signaling with the combination of TMZ and NVP-BEZ235 can be augmented beyond that achieved using each agent individually. In vivo xenograft models in mice, the combinatorial treatment with TMZ and NVP-BEZ235 significantly reduced tumor growth rates and prolonged median survival of tumor-bearing mice. These findings exhibit that TMZ in combination with NVP-BEZ235 act synergistically to inhibit proliferation of glioma cells by down-regulating of the PI3K-AKT-mTOR pathway, suggesting TMZ and NVP-BEZ235 combination therapy may be an option for GBM treatment.
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Obstetrics and Gynecology, First Hospital of Jilin University, Changchun, China.
authors.forename: Guifang
authors.initials: G
authors.lastname: Xie
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Guangtong
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Guangtao
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
authors.forename: Guangming
authors.initials: G
authors.lastname: Yao
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China. Electronic address: 664857729@qq.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China. Electronic address: 287348042@qq.com.
authors.forename: Yunqian
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, China. Electronic address: 13578924469@139.com.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008297:Male; D016513:Mice, SCID; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077204:Temozolomide; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; C494826:BAX protein, human; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D051028:bcl-2-Associated X Protein; D003606:Dacarbazine; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; C531198:dactolisib; D000077204:Temozolomide
keywords: Apoptosis; Cell cycle arrest; Glioma; NVP-BEZ235; PI3K–AKT–mTOR; Temozolomide