Telomerase inhibition and telomere targeting in hematopoietic cancer cell lines with small non-nucleosidic synthetic compounds (BIBR1532).
Telomere maintenance has been shown to be essential for unlimited growth potential of human cells and is regarded as one hallmark of cancer. Telomere repeats at the ends of eukaryotic chromosomes are synthesized by the enzyme telomerase, which is active in most cancers and to some extend also in normal somatic cells. Therefore, targeting the telomerase/telomere complex offers great potential for the development of novel anticancer therapeutics. An example of such a strategy is the small molecule BIBR1532 that is a selective, non-nucleosidic inhibitor of the catalytic component hTERT. Treatment of cancer cells with this compound leads to progressive telomere shortening, consecutive telomere dysfunction, and finally growth arrest after a lag period that is largely dependent on initial telomere length. We have additionally shown that using this class of telomerase inhibitor at higher concentrations exerts a direct cytotoxic effect on malignant cells of the hematopoietic system but not on normal stem cells, which appears to derive from direct damage to the structure of individual telomeres.
El Daly
Hesham
H
Department of Hematology/Oncology, Freiburg Medical University Center, Freiburg, Germany.
Martens
Uwe M
UM
D062365:Aminobenzoates / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000473:pathology; D008967:Molecular Biology / Q000379:methods*; D009281:Naphthalenes / Q000494:pharmacology*; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D062365:Aminobenzoates; C458523:BIBR 1532; D009281:Naphthalenes; D035341:Telomeric Repeat Binding Protein 2; D016159:Tumor Suppressor Protein p53; C509186:TERT protein, human; D019098:Telomerase