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

Yu, Zhiyun; Xie, Guifang; Zhou, Guangtong; Cheng, Ye; Zhang, Guangtao; Yao, Guangming; Chen, Yong; Li, Yunqian; Zhao, Gang

doi:10.1016/j.canlet.2015.07.007

Cited by 102 publications

(95 citation statements)

References 33 publications

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“…By using the 3’-UTR reporter assay, real-time qPCR, and immunoblotting assays, we observed that miR-128 directly targets and inhibits mTOR, RICTOR, IGF1, and PIK3R1 but not PDK1 expressions. Similar to findings in a previous study [40], our study results revealed that TMZ treatment alone significantly inhibited mTOR signaling. Furthermore, we observed that the overexpression or knockdown of miR-128 expression affected TMZ-repressed mTOR signaling, suggesting that miR-128-targeted mTOR signaling is involved in TMZ-mediated glioma cell death.…”

Section: Discussionsupporting

confidence: 91%

The Inhibition of microRNA-128 on IGF-1-Activating mTOR Signaling Involves in Temozolomide-Induced Glioma Cell Apoptotic Death

et al. 2016

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Temozolomide (TMZ), an alkylating agent of the imidazotetrazine series, is a first-line chemotherapeutic drug used in the clinical therapy of glioblastoma multiforme, the most common and high-grade primary glioma in adults. Micro (mi)RNAs, which are small noncoding RNAs, post-transcriptionally regulate gene expressions and are involved in gliomagenesis. However, no studies have reported relationships between TMZ and miRNA gene regulation. We investigated TMZ-mediated miRNA profiles and its molecular mechanisms underlying the induction of glioma cell death. By performing miRNA microarray and bioinformatics analyses, we observed that expression of 248 miRNAs was altered, including five significantly upregulated and 17 significantly downregulated miRNAs, in TMZ-treated U87MG cells. miR-128 expression levels were lower in different glioma cells and strongly associated with poor survival. TMZ treatment significantly upregulated miR-128 expression. TMZ significantly enhanced miR-128-1 promoter activity and transcriptionally regulated miR-128 levels through c-Jun N-terminal kinase 2/c-Jun pathways. The overexpression and knockdown of miR-128 expression significantly affected TMZ-mediated cell viability and apoptosis-related protein expression. Furthermore, the overexpression of miR-128 alone enhanced apoptotic death of glioma cells through caspase-3/9 activation, poly(ADP ribose) polymerase degradation, reactive oxygen species generation, mitochondrial membrane potential loss, and non-protective autophagy formation. Finally, we identified that key members in mammalian target of rapamycin (mTOR) signaling including mTOR, rapamycin-insensitive companion of mTOR, insulin-like growth factor 1, and PIK3R1, but not PDK1, were direct target genes of miR-128. TMZ inhibited mTOR signaling through miR-128 regulation. These results indicate that miR-128-inhibited mTOR signaling is involved in TMZ-mediated cytotoxicity. Our findings may provide a better understanding of cytotoxic mechanisms of TMZ involved in glioblastoma development.

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Section: Discussionsupporting

confidence: 91%

The Inhibition of microRNA-128 on IGF-1-Activating mTOR Signaling Involves in Temozolomide-Induced Glioma Cell Apoptotic Death

et al. 2016

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“…and Yu et al administered 25 mg/kg/day i.p. on mice with subcutaneous glioma tumours [28, 29]. Other dosage schedules have been used for other cancer types, although many use a different route of administration and/or time of exposure [30–36].…”

Section: Discussionmentioning

confidence: 99%

Dactolisib (NVP-BEZ235) toxicity in murine brain tumour models

et al. 2016

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BackgroundGlioblastomas (GBMs) are highly malignant brain tumours with a poor prognosis, and current cytotoxic regimens provide only a limited survival benefit. The PI3K/Akt/mTOR pathway has been an attractive target for therapy due to its high activation in GBMs as well as other cancers. The dual pan-PI3K/mTOR kinase inhibitor dactolisib (NVP-BEZ235) is an anti-neoplastic compound currently under investigation. However, little is known about its efficacy in human GBMs. We aimed at evaluating the efficacy of dactolisib in human glioblastoma cells, as well as in murine models carrying human GBM xenografts.MethodsTo assess the effect of dactolisib in vitro, MTS assay, manual cell count, BrdU incorporation and Annexin V staining experiments were used to observe growth and apoptosis. Furthermore, Akt phosphorylation (S473), a downstream target of PI3K, was explored by western blotting. Animal studies utilizing orthotopic xenograft models of glioblastoma were performed in nude rats and NOD/SCID mice to monitor survival benefit or inhibition of tumor growth.ResultsWe found that dactolisib in vitro shows excellent dose dependent anti-growth properties and increase in apoptosis. Moreover, dose dependent inhibition of Akt phosphorylation (S473), a downstream effect of PI3K, was observed by western blotting. However, in two independent animal studies utilizing nude rats and NOD/SCID mice in orthotopic xenograft models of glioblastoma, we observed no survival benefit or inhibition of tumour growth. Severe side effects were observed, such as elevated levels of blood glucose and the liver enzyme alanine transaminase (ALT), in addition to diarrhoea, hair loss (alopecia), skin rash and accumulation of saliva in the oral cavity.ConclusionTaken together, our results suggest that despite the anti-neoplastic efficacy of dactolisib in glioma treatment in vitro, its utility in vivo is questionable due to toxicity.

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“…22 In addition, increased levels of Bax and decreased levels of Bcl-2 have been indicated in glioma cell lines treated with BEZ235. 23 Based on the fact that tunicamycin exhibited similar effects as BEZ235 on inhibition of the PI3K/AKT/mTOR signaling pathway and stimulation of apoptosis, it was supposed that both chemicals might share similar mechanisms. With respect to autophagy, a recent study showed that tunicamycin enhanced conversion from LC3I to LC3II (autophagosome-associated form) and increased the Beclin1 levels, 24 which had also been described in this study.…”

Section: Discussionmentioning

confidence: 99%

Effects of endoplasmic reticulum stress on the autophagy, apoptosis, and chemotherapy resistance of human breast cancer cells by regulating the PI3K/AKT/mTOR signaling pathway

Zhong

Wang

et al. 2017

Tumour Biol.

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Nowadays, although chemotherapy is an established therapy for breast cancer, the molecular mechanisms of chemotherapy resistance in breast cancer remain poorly understood. This study aims to explore the effects of endoplasmic reticulum stress on autophagy, apoptosis, and chemotherapy resistance in human breast cancer cells by regulating PI3K/AKT/mTOR signaling pathway. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to detect the cell viability of six human breast cancer cell lines (MCF-7, ZR-75-30, T47D, MDA-MB-435s, MDA-MB-453, and MDA-MB-231) treated with tunicamycin (5 µM), after which MCF-7 cells were selected for further experiment. Then, MCF-7 cells were divided into the control (without any treatment), tunicamycin (8 µ), BEZ235 (5 µ), and tunicamycin + BEZ235 groups. Cell viability of each group was testified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Western blotting was applied to determine the expressions of endoplasmic reticulum stress and PI3K/AKT/mTOR pathwayrelated proteins and autophagy-and apoptosis-related proteins. Monodansylcadaverine and Annexin V-fluorescein isothiocyanate/propidium iodide staining were used for determination of cell autophagy and apoptosis. Furthermore, MCF-7 cells were divided into the control (without any treatment), tunicamycin (5 µM), cisplatin (16 µM), cisplatin (16 µM) + BEZ235 (5 µM), tunicamycin (5 µM) + cisplatin (16 µM), and tunicamycin (5 µM) + cisplatin (16 µM) + BEZ235 groups. Cell viability and apoptosis were also evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and Annexin V-fluorescein isothiocyanate/propidium iodide staining. In MCF-7 cells treated with tunicamycin, cell viability decreased significantly, but PEAK, eIF2, and CHOP were upregulated markedly and p-PI3K, p-AKT, and p-MTOR were downregulated in dose-and time-dependent manners. In the tunicamycin + BEZ235 group, the cell viability was lower and the apoptosis rate was higher than those of the control and monotherapy groups. Compared with the cisplatin group, the tunicamycin + cisplatin group showed a relatively higher growth inhibition rate; the growth inhibition rate substantially increased in the tunicamycin + cisplatin + BEZ235 group than the tunicamycin + cisplatin group. The apoptosis rate was highest in tunicamycin + cisplatin + BEZ235 group, followed by tunicamycin + cisplatin group and then cisplatin group. Our study provide evidence that endoplasmic reticulum stress activated by tunicamycin could promote breast cancer cell autophagy and apoptosis and enhance chemosensitivity of MCF-7 cells by inhibiting the PI3K/AKT/ mTOR signaling pathway.

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

Cited by 102 publications

References 33 publications

The Inhibition of microRNA-128 on IGF-1-Activating mTOR Signaling Involves in Temozolomide-Induced Glioma Cell Apoptotic Death

The Inhibition of microRNA-128 on IGF-1-Activating mTOR Signaling Involves in Temozolomide-Induced Glioma Cell Apoptotic Death

Dactolisib (NVP-BEZ235) toxicity in murine brain tumour models

Effects of endoplasmic reticulum stress on the autophagy, apoptosis, and chemotherapy resistance of human breast cancer cells by regulating the PI3K/AKT/mTOR signaling pathway

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