scholarly journals Identification of a quinoxaline derivative that is a potent telomerase inhibitor leading to cellular senescence of human cancer cells

2003 ◽  
Vol 373 (2) ◽  
pp. 523-529 ◽  
Author(s):  
Jun Hyun KIM ◽  
Joo Hee KIM ◽  
Gun Eui Lee ◽  
Sang Woong KIM ◽  
I. Kwon CHUNG

Telomere maintenance is essential for the continued proliferation of dividing cells, and is implicated in chromosome stability and cell immortalization. Telomerase activity allows cells to maintain their telomeric DNA and contributes to the indefinite replicative capacity of cancer cells. Telomerase is expressed in most cancer cells, but not in normal somatic cells, suggesting that telomerase is an attractive target for cancer chemotherapy. Here we screened a chemical library for inhibition of human telomerase, and identified 2,3,7-trichloro-5-nitroquinoxaline (TNQX) as a potent inhibitor. TNQX showed a potent inhibitory effect, with 50% inhibition at ~1.4 μM, and did not inhibit DNA and RNA polymerases, including retroviral reverse trancriptase. A series of enzyme kinetic experiments suggested that TNQX is a mixed-type non-competitive inhibitor, with an inhibitor-binding site distinct from the binding sites for the telomeric substrate (TS) primer and the dNTPs. Long-term cultivation of the MCF7 cell line with a drug concentration that did not cause acute cytotoxicity resulted in progressive telomere erosion followed by an increased incidence of chromosome abnormalities and induction of the senescence phenotype. The results presented here indicate that TNQX is a highly potent and selective anti-telomerase agent with good potential for further development as a promising anti-cancer agent.

2014 ◽  
Vol 30 (3) ◽  
pp. 345-353 ◽  
Author(s):  
Miriam Marlene Medina-Enríquez ◽  
Verónica Alcántara-Farfán ◽  
Leopoldo Aguilar-Faisal ◽  
José Guadalupe Trujillo-Ferrara ◽  
Lorena Rodríguez-Páez ◽  
...  

2005 ◽  
Vol 79 (2) ◽  
pp. 108-117 ◽  
Author(s):  
Xiaodong Xiao ◽  
Igor A. Sidorov ◽  
Jennifer Gee ◽  
Richard A. Lempicki ◽  
Dimiter S. Dimitrov

Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7139
Author(s):  
Pedro Novais ◽  
Patrícia M. A. Silva ◽  
Joana Moreira ◽  
Andreia Palmeira ◽  
Isabel Amorim ◽  
...  

Previously, we reported the in vitro growth inhibitory effect of diarylpentanoid BP-M345 on human cancer cells. Nevertheless, at that time, the cellular mechanism through which BP-M345 exerts its growth inhibitory effect remained to be explored. In the present work, we report its mechanism of action on cancer cells. The compound exhibits a potent tumor growth inhibitory activity with high selectivity index. Mechanistically, it induces perturbation of the spindles through microtubule instability. As a consequence, treated cells exhibit irreversible defects in chromosome congression during mitosis, which induce a prolonged spindle assembly checkpoint-dependent mitotic arrest, followed by massive apoptosis, as revealed by live cell imaging. Collectively, the results indicate that the diarylpentanoid BP-M345 exerts its antiproliferative activity by inhibiting mitosis through microtubule perturbation and causing cancer cell death, thereby highlighting its potential as antitumor agent.


2004 ◽  
Vol 36 (7) ◽  
pp. 492-500 ◽  
Author(s):  
Yi-Gang Wang ◽  
Jin-Hui Wang ◽  
Yan-Hong Zhang ◽  
Qing Gu ◽  
Xin-Yuan Liu

Abstract Telomerase activity is a wide tumor marker. Human telomerase reverse transcriptase (hTERT), the catalytic subunit of the telomerase, is transcriptionally upregulated exclusively in about 90% of cancer cells. In this study, we constructed a novel adeno-associated virus (AAV) vector containing the human interferon-β (hIFN-β) gene under the control of hTERT promoter (AAV-hTERT-hIFN-β) and investigated its antitumor effect against various human cancer cells in vitro. AAV-hTERT-hIFN-β displayed cancer-specific hIFN-β expression and cytotoxicity. The cytotoxic ratio was positively correlated with the time length of infection. AAV-hTERT-hIFN-β-mediated apoptotic morphology was observed by transmission electron microscopy. Flow cytometry assay also revealed that the cytotoxicity of AAV-hTERT-hIFN-β was mainly an apoptotic process. These data indicate that AAV in combination with hTERT-mediated therapeutic gene expression may open new possibilities for long-lasting and targeting gene therapy of varieties of cancers.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kohsuke Kato ◽  
Atsushi Kawaguchi ◽  
Kyosuke Nagata

AbstractTelomere, the terminus of linear chromosome in eukaryotes, is composed of specific repeat DNA which is mainly synthesized by a protein complex called telomerase. The maintenance of telomere DNA is important for unlimited proliferative capacity of cancer cells. The telomerase activity is controlled by the expression level of telomerase reverse transcriptase (TERT), a catalytic unit of telomerase, in some species including human. Therefore, to reveal the regulatory mechanisms of the transcription of TERT gene is important for understanding the tumor development. We found that template activating factor-I (TAF-I), a multifunctional nuclear protein, is involved in the transcriptional activation of TERT for the maintenance of telomere DNA in HeLa cells. TAF-I maintains the histone H3 modifications involved in transcriptional activation and hypomethylated cytosines in CpG dinucleotides around the transcription start site (TSS) in the TERT gene locus. Collectively, TAF-I is involved in the maintenance of telomere DNA through the regulation of TERT transcription, then consequently the occurrence and/or recurrence of cancer cells.


2007 ◽  
Vol 245 (1-2) ◽  
pp. 269-274 ◽  
Author(s):  
Mika Himeji ◽  
Takashi Ohtsuki ◽  
Harumi Fukazawa ◽  
Miho Tanaka ◽  
Shin-ichi Yazaki ◽  
...  

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