Telomere and telomerase as targets for anti-cancer and regeneration therapies

Hsu, Yi-Hsin; Lin, J. G.

doi:10.1111/j.1745-7254.2005.00098.x

Cited by 20 publications

(13 citation statements)

References 73 publications

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“…Telomerase is a ribonucleoprotein reverse transcriptase that is suppressed in normal somatic cells and is activated in cancer cells and immortalized cell lines (28). hTERT acts as a limiting factor for TA.…”

Section: Discussionmentioning

confidence: 99%

Curcumin Regulates Low-Linear Energy Transfer γ-Radiation-Induced NFκB-Dependent Telomerase Activity in Human Neuroblastoma Cells

Aravindan

Veeraraghavan

Madhusoodhanan

et al. 2011

International Journal of Radiation Oncology*Biology*Physics

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Purpose-We recently reported that curcumin attenuates radiation (IR) induced survival signaling and proliferation in human neuroblastoma (NB) cells. Also, in endothelial system, we demonstrated that NFκB regulates IR-induced telomerase activity (TA). Accordingly, we investigated the effect of curcumin in inhibiting IR-induced NFκB dependent hTERT transcription, TA and cell survival in NB cells.Methods and Materials-SK-N-MC or SH-SY5Y cells exposed to IR, treated with curcumin (10nM-100nM) with or without IR were harvested after 1h through 24h. NFκB dependent regulation was investigated either by luciferase reporter assays using pNFκB-, pGL3-354-, pGL3-347-, pUSE-IκBα-Luc, p50/p65 or RelA siRNA transfected cells. NFκB activity was analyzed using EMSA and hTERT expression using QPCR. TA was determined using TRAP assay and, cell survival using MTT and clonogenic assay.Results-Curcumin profoundly inhibited IR-induced NFκB. Consequently, curcumin significantly inhibited IR-induced TA and hTERT mRNA at all time points investigated. Furthermore, IR-induced TA is regulated at the transcriptional level by triggering TERT promoter activation. Moreover, NFκB becomes functionally activated after IR and mediates TA upregulation by binding to the κB-binding region in the promoter region of the TERT gene. Consistently, elimination of NFκB-recognition site on telomerase promoter or inhibition of NFκB by IκBα mutant compromises IR-induced telomerase promoter activation. Significantly, curcumin inhibited IR-induced TERT transcription. Consequently, Curcumin inhibited hTERT mRNA and TA in NFκB overexpressed cells. Furthermore, curcumin enhanced the IR-induced inhibition of cell survival.Conclusions-These results strongly suggest that curcumin inhibits IR-induced TA in an NFκB dependent manner in human NB cells.

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Section: Discussionmentioning

confidence: 99%

Curcumin Regulates Low-Linear Energy Transfer γ-Radiation-Induced NFκB-Dependent Telomerase Activity in Human Neuroblastoma Cells

Aravindan

Veeraraghavan

Madhusoodhanan

et al. 2011

International Journal of Radiation Oncology*Biology*Physics

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“…Although some tumors activated a yet unknown alternative mechanism of telomere extension, the majority (>90%) of human cancer cells acquire immortality by expression of the hTERT. It has been shown that hTERT expression is regulated at the transcriptional level, thereby providing a promising tool for tumor-specific gene expression (16,17).…”

mentioning

confidence: 99%

Increased Safety with Preserved Antitumoral Efficacy on Hepatocellular Carcinoma with Dual-Regulated Oncolytic Adenovirus

Zhang

Chen

Peng

et al. 2006

Clinical Cancer Research

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Purpose: A dual-regulated adenovirus variant CNHK500, in which human telomerase reverse transcriptase promoter drove the adenovirus 5 (Ad5) E1a gene and hypoxia-response promoter controlled the E1b gene, was engineered. This virus has broad anticancer spectrum and higher specificity compared with mono-regulated adenovirus CNHK300. The objective of the current study is to show its antitumor selectivity and therapeutic potential. Experimental Design: The antitumor specificity of human telomerase reverse transcriptase and hypoxia response promoters was evaluated in a panel of tumor and normal cells. Under the control of these promoters, the tumor-selective expression of E1a and E1b genes was evaluated. Further in vitro antitumor specificity and potency of this virus were characterized by viral replication and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Subsequently, hepatocellular carcinoma xenografts were established to evaluate CNHK500 antitumor efficacy in vivo by different routes of virus administration and different dosages. Results: Human telomerase reverse transcriptase and hypoxia response promoters were activated in a tumor-selective manner or under hypoxia treatment in a broad panel of cells. Selective adenoviral early gene expression, efficient viral replication, and oncolysis were observed in all tested cancer cells with more attenuated replication capacity in normal cells. Significant regression of hepatocellular carcinoma xenografts and prolonged survival were observed by either i.t. or i.v. administration. Conclusions: CNHK500 greatly reduced side effects in normal cells via dual control of adenoviral essential genes while still preserving potent antitumor efficacy on broad-spectrum cancer cells in vitro and in vivo. It can be used as a powerful therapeutic agent not only for liver cancers but also for other solid tumors.

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“…Accumulation of p53 protein in the nucleus induces a variety of downstream signaling pathways that mediate cellular responses to stress [5,14,19]. Therefore, p53 plays a crucial role in controlling cellular fate after irradiation [13,19].…”

Section: Discussionmentioning

confidence: 99%

“…Telomeres are specialized structures at the chromosome ends that are composed of TTAGGG repeated sequences, which interact with specific proteins and provide the protective caps of linear chromosomes [14]. The main functions of telomeres are to protect chromosome ends from deleterious DNA repair or recombination events and maintain the stability of the chromosome [5].…”

Section: Introductionmentioning

confidence: 99%

Radiosensitization to X-ray radiation by telomerase inhibitor MST-312 in human hepatoma HepG2 cells

et al. 2015

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Telomere and telomerase as targets for anti-cancer and regeneration therapies

Cited by 20 publications

References 73 publications

Curcumin Regulates Low-Linear Energy Transfer γ-Radiation-Induced NFκB-Dependent Telomerase Activity in Human Neuroblastoma Cells

Curcumin Regulates Low-Linear Energy Transfer γ-Radiation-Induced NFκB-Dependent Telomerase Activity in Human Neuroblastoma Cells

Increased Safety with Preserved Antitumoral Efficacy on Hepatocellular Carcinoma with Dual-Regulated Oncolytic Adenovirus

Radiosensitization to X-ray radiation by telomerase inhibitor MST-312 in human hepatoma HepG2 cells

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