Selective cytotoxicity and telomere damage in leukemia cells using the telomerase inhibitor BIBR1532.
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 nonnucleosidic small molecule inhibitor, BIBR1532 (2-[(E)-3-naphtalen-2-yl-but-2-enoylamino]-benzoic acid), has been identified that is highly selective for inhibition of telomerase, resulting in delayed growth arrest of tumor cells. Here we examined the effects of BIBR1532 in different leukemia cell lines as well as in primary cells from patients with acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) in short-term culture assays. We observed a dose-dependent direct cytotoxicity in concentrations ranging from 30 to 80 microM. Interestingly, cell death was not dependent on the catalytic activity of telomerase but was delayed in cells with very long telomeres. We observed time-dependent individual telomere erosion, which was associated with loss of telomeric repeat binding factor 2 (TRF2) and increased phosphorylation of p53. Importantly, the proliferative capacity of normal CD34(+) cells from cord blood and leukapheresis samples was not affected by treatment with BIBR1532. We conclude that using this class of telomerase inhibitor at higher concentrations exerts a direct cytotoxic effect on malignant cells of the hematopoietic system, which appears to derive from direct damage of the structure of individual telomeres and must be dissected from telomerase-suppressed overall telomere shortening.
El-Daly
Hesham
H
Freiburg University Medical Center, Department of Hematology/Oncology, Hugstetterstr 55, D-79106 Freiburg, Germany.
Kull
Miriam
M
Zimmermann
Stefan
S
Pantic
Milena
M
Waller
Cornelius F
CF
Martens
Uwe M
UM
D000208:Acute Disease; D062365:Aminobenzoates / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004171:Diploidy; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006131:Growth Inhibitors / Q000633:toxicity; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000201:enzymology* / Q000473:pathology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology / Q000473:pathology; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000473:pathology; D009281:Naphthalenes / Q000633:toxicity*; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D013997:Time Factors
D062365:Aminobenzoates; C458523:BIBR 1532; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D009281:Naphthalenes; D019098:Telomerase