Preclinical evaluation of a novel telomerase inhibitor in malignant cells of the hematopoietic system

Telomerase represents an attractive target for a mechanism-based therapeutic approach because its activation has been associated with unlimited proliferation in most cancer cells. Recently, a non-nucleosidic small molecule inhibitor, BIBR1532, has been identified which is highly selective for the inhibition of telomerase resulting in telomere dysfunction and delayed growth arrest in tumor cells. Here we examined the effects of BIBR1532 in different leukemia cell lines as well as in primary cells from patients with AML and CLL in short term culture assays. We observed a dose dependent direct cytotoxicity in concentrations ranging from 30 to 80 µM. Importantly, there was no effect on the in vitro proliferative capacity of normal CD34+ cells from cord blood and leukapheresis samples. Q-FISH analysis revealed that high concentrations of BIBR1532 induced a time-dependent individual telomere decapping which was associated with loss of TRF2 and increased phosphorylation of p53. Ectopic expression of hTERT revealed the close correlation of the protective role of the catalytic activity, telomere length and cellular stability. We conclude that High Dose BIBR1532 exerts a direct cytotoxic effect on malignant cells of the hematopoietic system which appears to be induce rapid sequestration of individual telomeres, the rate of proliferation plays also a crucial role in cells with longer telomeres.

Author dc:creator

• El Daly, Hesham

Contributors dc:contributor

• Martens, Uwe M.

• telomerase
• telomere
• TRF2
• telomere dysfunction
• leukemia

Repository record source_url

https://freidok.uni-freiburg.de/data/2097

OAI identifier oai:identifier

oai:freidok.uni-freiburg.de:2097