FK228 augmented temozolomide sensitivity in human glioma cells by blocking PI3K/AKT/mTOR signal pathways.

Temozolomide is a novel cytotoxic agent currently used as first-line chemotherapy for glioblastoma multiforme (GBM). Romidepsin (FK228), a histone deacetylase inhibitor, is a promising new class of antineoplastic agent with the capacity to induce growth arrest and/or apoptosis of cancer cells. However, combination of the two drugs in glioma remains largely unknown. In the present study, we evaluated the combinatory effects of FK228 with TMZ in glioma, and its molecular mechanisms responsible for these effects. Glioma cell lines were treated with TMZ, FK228 or the combination of drugs. The resistance effect including cytotoxicity and apoptosis was determined in glioma cells, respectively. We further evaluated the effects of FK228 in the PI3K/Akt-signaling pathway in vitro. Mice engrafted with 5×106 LN382 cells were treated with TMZ, FK228 or the combination of two drugs, and tumor weights and volumes were measured, respectively. FK228 enhanced the cytotoxic effects of TMZ in glioma cells compared to vehicle-treated controls or each drug alone. The combination of FK228 and TMZ-induced apoptosis was demonstrated by increased expression of cleaved-Caspase 3, Bax, cleaved-PARP, and decreased Bcl-2 expression. Furthermore, the expression of key components of the PI3K/Akt-signaling pathway showed that combination of FK228 and TMZ block PI3K/Akt pathways in vitro. This block effect was also confirmed in vivo in mice models. Mice treated with both FK228 and TMZ drugs showed significantly reduced tumor weights and volumes, compared to each drug alone. Our results suggested that FK228 augmented temozolomide sensitivity in human glioma cells partially by blocking PI3K/AKT/mTOR signal pathways. It thus may provide a promising target for improving the therapeutic outcome of TMZ-resistant gliomas, although further studies will be needed.

Wu Y ，Dong L ，Bao S ，Wang M ，Yun Y ，Zhu R ... -  《-》

NVP-BEZ235, a novel dual PI3K-mTOR inhibitor displays anti-glioma activity and reduces chemoresistance to temozolomide in human glioma cells.

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.

Yu Z ，Xie G ，Zhou G ，Cheng Y ，Zhang G ，Yao G ，Chen Y ，Li Y ，Zhao G ... -  《-》

Inhibition of PI3K/AKT/mTOR pathway enhances temozolomide-induced cytotoxicity in pituitary adenoma cell lines in vitro and xenografted pituitary adenoma in female nude mice.

Dai C ，Zhang B ，Liu X ，Ma S ，Yang Y ，Yao Y ，Feng M ，Bao X ，Li G ，Wang J ，Guo K ，Ma W ，Xing B ，Lian W ，Xiao J ，Cai F ，Zhang H ，Wang R ... -  《-》

Cordycepin Augments the Chemosensitivity of Human Glioma Cells to Temozolomide by Activating AMPK and Inhibiting the AKT Signaling Pathway.

Bi Y ，Li H ，Yi D ，Sun Y ，Bai Y ，Zhong S ，Song Y ，Zhao G ，Chen Y ... -  《-》

Enhanced cytotoxic effect of radiation and temozolomide in malignant glioma cells: targeting PI3K-AKT-mTOR signaling, HSP90 and histone deacetylases.

Choi EJ ，Cho BJ ，Lee DJ ，Hwang YH ，Chun SH ，Kim HH ，Kim IA ... -  《BMC CANCER》