LY294002 enhances cytotoxicity of temozolomide in glioma by down-regulation of the PI3K/Akt pathway

Chen, Lingchao; Han, Lei; Shi, Zhendong; Zhang, Kailiang; Liu, Yanwei; Zheng, Yongri; Jiang, Tao; Pu, Peiyu; Jiang, Chuanlu; Kang, Chunsheng

doi:10.3892/mmr.2011.674

Cited by 22 publications

(16 citation statements)

References 22 publications

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“…In addition, TMZ combined with amlexanox e caciously reduced the tumor volume and improved the survival of mice in the xenograft model in vivo. To date, a growing number of studies have focused on the inhibition of the AKT signaling pathway with combined administration in GBM and other tumors [7,[29][30][31][32][33][34]. Zhiyun Yu and his colleagues suggested that TMZ combined with NVP-BEZ235 synergistically inhibited GBM cell proliferation though downregulating AKT/mTOR signaling pathway [4], which was similar to our ndings.…”

Section: Discussionsupporting

confidence: 85%

Amlexanox enhances temozolomide-induced anti-tumor effects in human glioblastoma cells by inhibiting IKBKE and the Akt-mTOR signaling pathway

Xiong

Guo

et al. 2020

Preprint

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Background: Temozolomide (TMZ), as the first-line chemotherapeutic agent for the treatment of glioblastoma multiforme (GBM), often fails to improve the prognosis of GBM patients due to the quick development of resistance. The need for more effective management of GBM is urgent. The aim of this study is to evaluate the efficacy of combined therapy with TMZ and amlexanox, a selective inhibitor of inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKBKE), for GBM. Methods: in vitro, cell viability assay, apoptosis analysis, western blot, migration and invasion assay were used. In vivo, intracranial tumor models were constructed and the immunohistochemistry were used. Results: We found that combined treatment resulted in significant induction of cellular apoptosis and the inhibition of cell viability, migration and invasion in primary glioma cell and in the human glioma cell line, U87 MG. TMZ enhanced expression of phosphoration of adenosine 5‘-monophosphate-activated protein kinase (p-AMPK) and amlexanox led to reduction of IKBKE, with no impact on p-AMPK. Furthermore, we demonstrated that, compared to other groups treated with each component alone, TMZ combined with amlexanox effectively inhibited phosphorylation of protein kinase B (AKT) and mammalian target of rapamycin (mTOR). In addition, the combination treatment also clearly reduced in vivo tumor volume and prolonged median survival time in the xenograft mouse model. Conclusion: These results suggest that amlexanox sensitized primary glioma cell and U87 MG cell to TMZ at least partially though the suppression of IKBKE activation and the attenuation of AKT activation. Overall, combined treatment with TMZ and amlexanox may provide a promising possibility for improving the prognosis of glioblastoma patients in clinical practice.

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Section: Discussionsupporting

confidence: 85%

Amlexanox enhances temozolomide-induced anti-tumor effects in human glioblastoma cells by inhibiting IKBKE and the Akt-mTOR signaling pathway

Xiong

Guo

et al. 2020

Preprint

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“…TMZ induced AKT activation, as well as deactivated mTOR. It has proved that inhibition of AKT expression was accompanied by a significant increased in glioma cell sensitivity to TMZ [ 9 , 13 ]. These results strongly support the hypothesis that clinical benefits are obtained by combining TMZ with inhibitors of the AKT-mTOR pathway.…”

Section: Discussionmentioning

confidence: 99%

“…AKT activation is also correlated with the increased tumorigenicity, invasiveness and stemness [ 7 ]. It has demonstrated that cancer stem cells are preferentially sensitive to an inhibitor of AKT [ 8 , 12 ] and down-regulation of the AKT pathway can enhance the cytotoxicity of TMZ [ 9 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Metformin and temozolomide act synergistically to inhibit growth of glioma cells and glioma stem cellsin vitroandin vivo

Zhao

Xie

et al. 2015

Oncotarget

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Glioblastoma (GBM) is the most frequent and aggressive brain tumor in adults. In spite of advances in diagnosis and therapy, the prognosis of patients with GBM has remained dismal. The fast recurrence and multi-drug resistance are some of the key challenges in combating brain tumors. Glioma stem cells (GSCs) which are considered the source of relapse and chemoresistance, the need for more effective therapeutic options is overwhelming. In our present work, we found that combined treatment with temozolomide (TMZ) and metformin (MET) synergistically inhibited proliferation and induced apoptosis in both glioma cells and GSCs. Combination of TMZ and MET significantly reduced the secondary gliosphere formation and expansion of GSCs. We first demonstrated that MET effectively inhibited the AKT activation induced by TMZ, and a combination of both drugs led to enhanced reduction of mTOR, 4EBP1 and S6K phosphorylation. In addition, the combination of the two drugs was accompanied with a powerful AMP-activated protein kinase (AMPK) activation, while this pathway is not determinant. Xenografts performed in nude mice demonstrate in vivo demonstrated that combined treatment significantly reduced tumor growth rates and prolonged median survival of tumor-bearing mice. In conclusion, TMZ in combination with MET synergistically inhibits the GSCs proliferation through downregulation of AKT-mTOR signaling pathway. The combined treatment of two drugs inhibits GSCs self-renewal capability and partly eliminates GSCs in vitro and in vivo. This combined treatment could be a promising option for patients with advanced GBM.

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“…Akt activation is correlated with the increased tumorigenicity, invasiveness and stemness ( 6 ) and overexpression of an active form of Akt increases glioma cell resistance to TMZ ( 5 , 8 ). It has demonstrated that cancer stem cells are preferentially sensitive to an inhibitor of Akt ( 7 , 10 ) and down-regulation of the PI3K/Akt pathway enhances the cytotoxicity of TMZ ( 11 ). At present, the most effective drug for the treatment of glioblastoma is TMZ, the primary path leading to glioma cell death is formation of O-6-methylguanine and apoptotic signalling triggered by O-6-methyl G:T mispairs, but apoptotic signalling goes through a step mediated by AMPK ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Temozolomide in combination with metformin act synergistically to inhibit proliferation and expansion of glioma stem-like cells

Zhao

et al. 2016

Oncology Letters

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Glioblastoma is the most common and most aggressive brain tumor in adults. The introduction of temozolomide (TMZ) has advanced chemotherapy for malignant gliomas, but it is not curative. The difficulties in treating glioblastoma may be as a result of the presence of glioma stem cells (GSCs), which are a source of relapse and chemoresistance. Another reason may be that endogenous Akt kinase activity may be activated in response to clinically relevant concentrations of TMZ. Akt activation is correlated with the increased tumorigenicity, invasiveness and stemness of cancer cells and overexpression of an active form of Akt increases glioma cell resistance to TMZ. Mounting evidence has demonstrated that cancer stem cells are preferentially sensitive to an inhibitor of Akt and down-regulation of the PI3K/Akt pathway may enhance the cytotoxicity of TMZ. Metformin (MET), the first-line drug for treating diabetes, it has been proved that it reduces AKT activation and selectively kills cancer stem cells, but whether it can potentiate the cytotoxicity of TMZ for GSCs remains unknown. In the present study, the GSCs isolated from human glioma cell line U87 and Rat glioma cell line C6, in vitro treatment with TMZ either alone or with MET. The present study demonstrates that MET acts synergistically with TMZ in inhibiting GSCs proliferation and generating the highest apoptotic rates when compared to either drug alone. These findings implicate that GSCs cytotoxicity mediated by TMZ may be stimulated by MET, have a synergistic effect, but the definite mechanisms remain elusive.

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LY294002 enhances cytotoxicity of temozolomide in glioma by down-regulation of the PI3K/Akt pathway

Cited by 22 publications

References 22 publications

Amlexanox enhances temozolomide-induced anti-tumor effects in human glioblastoma cells by inhibiting IKBKE and the Akt-mTOR signaling pathway

Amlexanox enhances temozolomide-induced anti-tumor effects in human glioblastoma cells by inhibiting IKBKE and the Akt-mTOR signaling pathway

Metformin and temozolomide act synergistically to inhibit growth of glioma cells and glioma stem cellsin vitroandin vivo

Temozolomide in combination with metformin act synergistically to inhibit proliferation and expansion of glioma stem-like cells

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