Abstract
Since unlimited proliferative potential has been identified as a major and, to date, therapeutically unexploited phenotypic hallmark of cancer, telomere maintenance mechanisms have been proposed as potential targets for new anticancer interventions. This study was aimed to investigate the effects of BIBR1532, the lead compound of non-nucleosidic inhibition of telomerase, on pre-B acute lymphoblastic leukemia (ALL) cells. BIBR1532 caused rapid cell death in Nalm-6 cells probably through transcriptional suppression of survivin-mediated c-Myc and human telomerase reverse transcriptase (hTERT) expression in a concentration-dependent manner. Moreover, our results also suggest that induced p73, up-regulated Bax/Bcl-2 molecular ratio and subsequent activation of caspase-3 may contribute to a direct short-term cytotoxic effect of high doses of BIBR1532, independent of long-term substantial telomere erosion-mediated cell cycle arrest.
MeSH terms
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Aminobenzoates / pharmacology*
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Apoptosis / drug effects*
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Caspase 3 / genetics
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Caspase 3 / metabolism
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Cell Cycle Checkpoints / drug effects
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Cell Cycle Checkpoints / genetics
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / genetics
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Dose-Response Relationship, Drug
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Gene Expression Regulation, Leukemic / drug effects
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Humans
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism
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Naphthalenes / pharmacology*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-myc / genetics
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Proto-Oncogene Proteins c-myc / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Survivin
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Telomerase / antagonists & inhibitors*
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Telomerase / genetics
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Telomerase / metabolism
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Tumor Protein p73
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism
Substances
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Aminobenzoates
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BIBR 1532
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BIRC5 protein, human
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DNA-Binding Proteins
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Inhibitor of Apoptosis Proteins
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MYC protein, human
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Naphthalenes
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Nuclear Proteins
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Proto-Oncogene Proteins c-bcl-2
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Proto-Oncogene Proteins c-myc
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Survivin
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TP73 protein, human
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Tumor Protein p73
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Tumor Suppressor Proteins
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bcl-2-Associated X Protein
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Telomerase
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Caspase 3