Arginine butyrate downregulates p210 bcr-abl expression and induces apoptosis in chronic myelogenous leukemia cells.
Downregulation of bcr-abl expression in the chronic myelogenous leukemia cell line K562 using antisense oligonucleotides has been shown to enhance the sensitivity of the cells to apoptotic stimuli, suggesting that p210 bcr-abl, like bcl-2 functions as an anti-apoptosis factor (McGahon A et al, Blood 1994, 83: 1179). In these experiments, the inhibition of p210 bcr-abl expression alone was not sufficient to induce apoptosis. We demonstrated that exposure to low doses (0.5 mM) of a butyric acid analog, arginine butyrate, was capable of inducing apoptosis in selected leukemia cell lines, including K562 cells, and in fresh leukemia cells from patients with chronic myelogenous leukemia. To further explore the mechanisms of this effect, we examined expression of p210 bcr-abl after butyrate exposure and found a dose-related inhibition of p210 bcr-abl protein without concordant change in other phosphoproteins, including the JAK-1 kinase. Further analysis revealed that the inhibition of bcr-abl expression occurs due to transcriptional regulation of the bcr-abl gene by arginine butyrate. These results suggest that arginine butyrate and other butyrate analogs alone or in combination may be useful in the therapy of patients with chronic myelogenous leukemia or bcr-abl expressing acute leukemias.
Urbano
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Section of Hematology-Oncology and Biomolecular Medicine, Evans Research Foundation, Boston University Medical Center, MA, USA.
Koc
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Foss
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D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology*; D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D053613:Janus Kinase 1; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002087:Butyrates; D001120:Arginine; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C507904:JAK1 protein, human; D053613:Janus Kinase 1; C033018:arginine butyrate