Butylidenephthalide Suppresses Human Telomerase Reverse Transcriptase (TERT) in Human Glioblastomas

Lin, Shinn Zong; Chen, Yi Lin; Chang, Jeng Shou; Ho, Ling‐Jun; Liu, Po Yen; Chang, Lin‐Li; Harn, Yeu Chern; Chen, Shee Ping; Sun, Li; Huang, Pi Chun; Chein, Jung Ting; Tsai, Chang Hai; Chou, Chii Wen; Harn, Horng Jyh; Chiou, Tzyy Wen

doi:10.1245/s10434-011-1644-0

Cited by 26 publications

(26 citation statements)

References 48 publications

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“…We have demonstrated previously that BP has antitumor effects on GBM brain tumors [34,35,36]. Moreover, BP inhibited telomerase activity and promoted senescence in GBM cells [37,38]. Temozolomide (TMZ) drug resistance is a major problem in the treatment of glioblastoma.…”

Section: Introductionmentioning

confidence: 99%

n-Butylidenephthalide Regulated Tumor Stem Cell Genes EZH2/AXL and Reduced Its Migration and Invasion in Glioblastoma

Yen

Chuang

Huang

et al. 2017

IJMS

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Glioblastoma (GBM) is one of the most common and aggressive types of brain tumor. Due to its highly recurrent rate and poor prognosis, the overall survival time with this type of tumor is only 20–21 months. Recent knowledge suggests that its recurrence is in part due to the presence of cancer stem cells (CSCs), which display radioresistant, chemoresistant, self-renewal and tumorigenic potential. Enhancers of Zeste 2 (EZH2) and AXL receptor tyrosine kinase (AXL) are both highly expressed in GBM. Additionally, they are an essential regulator involved in CSCs maintenance, migration, invasion, epithelial-to-mesenchymal transition (EMT), stemness, metastasis and patient survival. In this study, we used a small molecule, n-butylidenephthalide (BP), to assess the anti-GBM stem-like cells potential, and then tried to find out the associated genes involved with regulation in migration and invasion. We demonstrated that BP reduced the expression of AXL and stemness related genes in a dose-dependent manner. The migratory and invasive capabilities of GBM stem-like cells could be reduced by AXL/EZH2. Finally, in the overexpression of AXL, EZH2 and Sox2 by transfection in GBM stem-like cells, we found that AXL/EZH2/TGF-β1, but not Sox2, might be a key regulator in tumor invasion, migration and EMT. These results might help in the development of a new anticancer compound and can be a target for treating GBM.

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Section: Introductionmentioning

confidence: 99%

n-Butylidenephthalide Regulated Tumor Stem Cell Genes EZH2/AXL and Reduced Its Migration and Invasion in Glioblastoma

Yen

Chuang

Huang

et al. 2017

IJMS

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“…hTERT expression is strongly associated with GBM (4), and patients with high hTERT levels have very short survival (5). Suppression of hTERT in GBM cells induces senescence and inhibits proliferation (6). The telomerase antagonist, imetelstat, can inhibit GBM growth, showing an increased efficacy in combination with radiation and temozolomide (7).…”

Section: Introductionmentioning

confidence: 99%

Telomere Targeting with a New G4 Ligand Enhances Radiation-Induced Killing of Human Glioblastoma Cells

Merle

Evrard

Petitjean

et al. 2011

Molecular Cancer Therapeutics

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The aim of this study was to test in vitro the efficacy of TAC, an original G-quadruplex ligand, as a potential radiosensitizing agent for glioblastoma multiforme (GBM). Two human radioresistant telomerase-positive GBM cell lines (SF763 and SF767) were analyzed, with and without TAC treatment, for telomere length, cell proliferation, apoptosis, cell-cycle distribution, gene expression, cytogenetic aberrations, clonogenic survival assay, 53BP1 immunofluorescence staining, and gH2AX phosphorylation. We found that low concentrations of TAC (0.5 and 1 mmol/L) inhibited the proliferation of GBM cells in a concentration-dependent manner after only 1 week of treatment, with minimal effects on cell cycle and apoptosis. TAC treatment had no visible effect on average telomere length but modified expression levels of telomere-related genes (hTERT, TRF1, and TRF2) and induced concentration-dependent DNA damage response and dicentric chromosomes. Survival curves analysis showed that exposure to nontoxic, subapoptotic concentrations of TAC enhanced radiation-induced killing of GBM cells. Analysis of DNA repair after irradiation revealed delayed repair kinetics in GBM cells treated with TAC. Furthermore, the combined treatment (TAC and radiation) significantly increased the frequency of chromosomal aberrations as compared with radiation alone. These findings provide the first evidence that exposure to a G4 ligand radiosensitizes human glioblastoma cells and suggest the prospect of future therapeutic applications. Mol Cancer Ther; 10(10); 1784-95. Ó2011 AACR.

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“…The natural compound n-butylidenephthalide (BP), isolated from the chloroform extract of Angelica sinensis, has been reported to have antitumor activity in glioblastoma multiforme (GBM), [1][2][3][4] prostate cancer, 5,6 oral squamous cell carcinoma, 7 lung cancer, 8 and hepatoma. 9 In particular, BP has been developed to treat brain tumors due to its ability to permeate through the blood-brain barrier and enter into the brain.…”

Section: Introductionmentioning

confidence: 99%

“…2 BP inhibits telomerase activity by repressing hTERT transcriptional activity via the downregulation of Sp1 or AP-2 expression. 3,8 BP also regulates the eFAS-dependent pathway, the mitochondrial pathway, and the ER stress pathway that is involved in cell apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Liposomal n-butylidenephthalide protects the drug from oxidation and enhances its antitumor effects in glioblastoma multiforme

Lin¹,

Chang²,

Huang³

et al. 2015

IJN

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Background The natural compound n -butylidenephthalide (BP) can pass through the blood–brain barrier to inhibit the growth of glioblastoma multiforme tumors. However, BP has an unstable structure that reduces its antitumor activity and half-life in vivo. Objective The aim of this study is to design a drug delivery system to encapsulate BP to enhance its efficacy by improving its protection and delivery. Methods To protect its structural stability against protein-rich and peroxide solutions, BP was encapsulated into a lipo-PEG-PEI complex (LPPC). Then, the cytotoxicity of BP/LPPC following preincubation in protein-rich, acid/alkaline, and peroxide solutions was analyzed by MTT. Cell uptake of BP/LPPC was also measured by confocal microscopy. The therapeutic effects of BP/LPPC were analyzed in xenograft mice following intratumoral and intravenous injections. Results When BP was encapsulated in LPPC, its cytotoxicity was maintained following preincubation in protein-rich, acid/alkaline, and peroxide solutions. The cytotoxic activity of encapsulated BP was higher than that of free BP (~4.5- to 8.5-fold). This increased cytotoxic activity of BP/LPPC is attributable to its rapid transport across the cell membrane. In an animal study, a subcutaneously xenografted glioblastoma multiforme mouse that was treated with BP by intratumoral and intravenous administration showed inhibited tumor growth. The same dose of BP/LPPC was significantly more effective in terms of tumor inhibition. Conclusion LPPC encapsulation technology is able to protect BP’s structural stability and enhance its antitumor effects, thus providing a better tool for use in cancer therapy.

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Butylidenephthalide Suppresses Human Telomerase Reverse Transcriptase (TERT) in Human Glioblastomas

Abstract: These findings suggest that BP inhibits proliferation and induces senescence in human glioblastomas by downregulating hTERT expression and consequently telomerase activity. This is the first study to describe regulation of telomerase activity by BP in human glioblastomas.

Cited by 26 publications

References 48 publications

n-Butylidenephthalide Regulated Tumor Stem Cell Genes EZH2/AXL and Reduced Its Migration and Invasion in Glioblastoma

n-Butylidenephthalide Regulated Tumor Stem Cell Genes EZH2/AXL and Reduced Its Migration and Invasion in Glioblastoma

Telomere Targeting with a New G4 Ligand Enhances Radiation-Induced Killing of Human Glioblastoma Cells

Liposomal n-butylidenephthalide protects the drug from oxidation and enhances its antitumor effects in glioblastoma multiforme

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