Downregulation of HIF-1a sensitizes U251 glioma cells to the temozolomide (TMZ) treatment

Tang, Jun; Ma, Zhixiong; Huang, Guo‐Hao; Xu, Qing; Yan, Xiang; Li, Ningning; Sidlauskas, Kastytis; Zhang, Eric Erquan; Lv, Sheng‐Qing

doi:10.1016/j.yexcr.2016.04.011

Cited by 36 publications

(29 citation statements)

References 48 publications

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“…Zou et al (26) identified that TMZ inhibited the growth of glioma cells and decreased the number of cells in S and G 2 /M, leading to atypical cell apoptosis. The present study identified that the use of TMZ alone to treat U251 cells induces a slight increase in autophagy-related proteins and may induce the apoptosis of glioma cells to a certain extent, which is consistent with a previous study (15). mTOR is a central regulator of cell growth, proliferation, survival, migration, self-renewal and cell cycle progression (27)(28)(29).…”

Section: Discussionsupporting

confidence: 92%

“…This red fluorescence appears when acid phosphatase activity increases during autolysosome formation. The present experiment was performed as described in a previous study, which used the FL1 pathway to detect green fluorescence with an emission maximum at 532 nm and the FL3 pathway to detect red fluorescence by using 6HFFRPWL Shower Lens, in order to analyze AVO generation in U251 cells (15). U251 cells in the logarithmic phase of growth (1x10 4 cells/ml), were inoculated into a 24-well plate (1 ml/well).…”

Section: Methodsmentioning

confidence: 99%

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Effect and molecular mechanism of mTOR inhibitor rapamycin on temozolomide‑induced autophagic death of U251 glioma cells

Zhou

et al. 2017

Oncol Lett

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Abstract. Glioma is a malignant tumor of the glial tissue that is difficult to excise through surgery, with poor patient prognosis. The use of chemotherapeutic drugs alone to treat glioma following surgery results in a high probability of sequelae, such as tumor recurrence. The present study investigated the effects of a novel treatment combination on glioma cells and determined the molecular mechanisms underlying its action. The effect of temozolomide (TMZ) combined with rapamycin (RAPA) on the TMZ-induced autophagic death of U251 glioma cells was examined. The U251 cell line was treated with TMZ combined with RAPA, and the cell survival rate and half maximal inhibitory concentration (IC 50 ) of TMZ/RAPA was detected using the Cell Counting Kit-8 (CCK-8) assay. Flow cytometry was used to detect changes in cell cycle distribution. The formation of acidic vesicular organelles (AVOs) in the cytoplasm was identified using fluorescence microscopy and quantitatively analyzed. Western blotting was performed to detect the expression levels of autophagy-associated proteins Beclin-1 and microtubule associated protein 1 light chain 3 alpha (MAP1LC3A)-I and II. RAPA (1.25 nM) combined with 5 µM TMZ markedly inhibited U251 cell growth. RAPA reinforced TMZ-induced autophagic death, reducing the IC 50 value of treatment when combined (TMZ alone, 22.5±3.23 µM vs. TMZ and RAPA, 10.35±2.81 µM). Compared with the control group, the proportion of cells in G 2 /M were markedly increased following treatment with TMZ combined with RAPA. Acridine orange staining demonstrated that TMZ combined with RAPA could markedly enhance the generation of intracellular AVOs compared with TMZ or RAPA alone. In addition, Beclin-1 and LC3-II protein expression was markedly increased compared with the control and single treatment groups (P<0.05). The results of the present study indicate that RAPA reinforces TMZ-induced autophagic death of U251 glioma cells, providing a novel therapeutic combination for the treatment of malignant glioma.

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Effect and molecular mechanism of mTOR inhibitor rapamycin on temozolomide‑induced autophagic death of U251 glioma cells

Zhou

et al. 2017

Oncol Lett

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“…HIF-1α is most important in correlation with metastasis, prognostic outcomes in cancers. Knockdown of HIF-1α remarkably enhances drug sensitivity and reduces tumor invasion and metastasis in glioma cells [55]. Studies have established the decisive role of HIF in EMT under the condition of hypoxia through the direct regulation of ZEB1 in glioma [56].…”

Section: Emt Microenvironment In Gliomamentioning

confidence: 99%

The progression of epithelial-mesenchymal transformation in gliomas

Tang

Huang

et al. 2017

Chin Neurosurg Jl

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Epithelial-mesenchymal transformation(EMT) is a coordinated process in which polarized epithelial cells are induced to lose adhesion from the basement membrane and obtain the properties of mesenchymal cells, including invasion and metastasis. It has been proved that EMT greatly contributes to the invasion and therapeutic resistance of various solid human cancers. However, the role of EMT in brain glioma has not yet been fully clarified. So in this review, we mainly elaborate the latest progression about the related regulatory transcription factors, key signaling pathways and microRNAs (miRNAs) of EMT in gliomas.

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“…If the MGMT promoter is methylated, the gene is silenced . Otherwise, the gene will be expressed, and the expression efficiency is modulated by many mechanisms, including the hypoxia‐inducible factor‐1‐alpha (HIF‐1α), NF‐κB, and WNT/β‐catenin pathways …”

Section: Introductionmentioning

confidence: 99%

“…Of late, Tang et al reported that the HIF‐1α inhibitor 2‐methoxyestradiol (2‐ME) downregulated MGMT expression under hypoxic conditions. However, 2‐ME is highly cytotoxic, which limits further investigation in preclinical settings, and it only exerts an effect under hypoxic conditions . FM19G11 is a novel small molecule (molecular weight: 463.40 g/mol) HIF‐1α inhibitor with an effective dose in the nanomolar range, and it is very safe at concentrations lower than 30 μmol/L .…”

Section: Introductionmentioning

confidence: 99%

FM19G11 inhibits O⁶‐methylguanine DNA‐methyltransferase expression under both hypoxic and normoxic conditions

et al. 2018

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FM19G11 is a small molecular agent that inhibits hypoxia‐inducible factor‐1‐alpha (HIF‐1α) and other signaling pathways. In this study, we characterized the modulating effects of FM19G11 on O6‐methylguanine DNA‐methyltransferase (MGMT), the main regulator of temozolomide (TMZ) resistance in glioblastomas. This study included 2 MGMT‐positive cell lines (GBM‐XD and T98G). MGMT promoter methylation status, mRNA abundance, and protein levels were determined before and after FM19G11 treatment, and the roles of various signaling pathways were characterized. Under hypoxic conditions, MGMT mRNA and protein levels were significantly downregulated by FM19G11 via the HIF‐1α pathway in both GBM‐XD and T98G cells. In normoxic culture, T98G cells were strongly positive for MGMT, and MGMT expression was substantially downregulated by FM19G11 via the NF‐κB pathway. In addition, TMZ resistance was reversed by treatment with FM19G11. Meanwhile, FM19G11 has no cytotoxicity at its effective dose. FM19G11 could potentially be used to counteract TMZ resistance in MGMT‐positive glioblastomas.

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Downregulation of HIF-1a sensitizes U251 glioma cells to the temozolomide (TMZ) treatment

Cited by 36 publications

References 48 publications

Effect and molecular mechanism of mTOR inhibitor rapamycin on temozolomide‑induced autophagic death of U251 glioma cells

Effect and molecular mechanism of mTOR inhibitor rapamycin on temozolomide‑induced autophagic death of U251 glioma cells

The progression of epithelial-mesenchymal transformation in gliomas

FM19G11 inhibits O⁶‐methylguanine DNA‐methyltransferase expression under both hypoxic and normoxic conditions

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Downregulation of HIF-1a sensitizes U251 glioma cells to the temozolomide (TMZ) treatment

Cited by 36 publications

References 48 publications

Effect and molecular mechanism of mTOR inhibitor rapamycin on temozolomide‑induced autophagic death of U251 glioma cells

Effect and molecular mechanism of mTOR inhibitor rapamycin on temozolomide‑induced autophagic death of U251 glioma cells

The progression of epithelial-mesenchymal transformation in gliomas

FM19G11 inhibits O6‐methylguanine DNA‐methyltransferase expression under both hypoxic and normoxic conditions

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FM19G11 inhibits O⁶‐methylguanine DNA‐methyltransferase expression under both hypoxic and normoxic conditions