A highly selective telomerase inhibitor limiting human cancer cell proliferation
| Autor: | Norbert Hauel, Ines Lauritsch, Bernd Guilliard, Andreas Schnapp, Iris Kauffmann, Joachim Lingner, Uwe M. Martens, Ulrike Hemmann, Christian Wenz, Barbara Enenkel, Claudia Niestroj, Wolfgang J. Rettig, Milena Pantic, Henning Priepke, Emanuelle Pascolo, Pilar Garin-Chesa, Norbert Kraut, Elfriede Müller, Gabriele Sauter, Klaus Damm, Christine Daiber |
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| Rok vydání: | 2001 |
| Předmět: |
Telomerase
Cell division Biology Article General Biochemistry Genetics and Molecular Biology Germline Neoplasms Tumor Cells Cultured Humans Telomerase reverse transcriptase RNA Messenger Enzyme Inhibitors Molecular Biology Oligonucleotide Array Sequence Analysis Ribonucleoprotein General Immunology and Microbiology Reverse Transcriptase Polymerase Chain Reaction Cell growth Gene Expression Profiling General Neuroscience Telomere Molecular biology Cancer cell Cancer research Cell Division |
| Zdroj: | The EMBO Journal. 20:6958-6968 |
| ISSN: | 1460-2075 |
| Popis: | Telomerase, the ribonucleoprotein enzyme maintaining the telomeres of eukaryotic chromosomes, is active in most human cancers and in germline cells but, with few exceptions, not in normal human somatic tissues. Telomere maintenance is essential to the replicative potential of malignant cells and the inhibition of telomerase can lead to telomere shortening and cessation of unrestrained proliferation. We describe novel chemical compounds which selectively inhibit telomerase in vitro and in vivo. Treatment of cancer cells with these inhibitors leads to progressive telomere shortening, with no acute cytotoxicity, but a proliferation arrest after a characteristic lag period with hallmarks of senescence, including morphological, mitotic and chromosomal aberrations and altered patterns of gene expression. Telomerase inhibition and telomere shortening also result in a marked reduction of the tumorigenic potential of drug-treated tumour cells in a mouse xenograft model. This model was also used to demonstrate in vivo efficacy with no adverse side effects and uncomplicated oral administration of the inhibitor. These findings indicate that potent and selective, non-nucleosidic telomerase inhibitors can be designed as novel cancer treatment modalities. |
| Databáze: | OpenAIRE |
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