Arginine butyrate downregulates p210 bcr-abl expression and induces apoptosis in chronic myelogenous leukemia cells

Abstract

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 p 210 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 p 210 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 p 210 bcr-abl after butyrate exposure and found a dose-related inhibition of p 210 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.

c-Kit and c-kit mutations in mastocytosis and other hematological diseases

“…The third question is related to present knowledge regarding physiopathology of myeloproliferative syndromes. Indeed, regarding CML, it is hypothesized that bcr/abl hybrid might confer to the leukemic clone an advantage in term of survival (i.e., decreased apoptosis) more than in terms of proliferation [122][123][124][125]. Such a mechanism could also be involved in the abnormal accumulation of mast cells in mastocytosis.…”

Modulation of cell cycle-related protein expression by sodium butyrate in human non-small cell lung cancer cell lines

“…[7][8][9] By contrast, little information is available on NaB-induced alterations of proliferation-related proteins in lung cancer, a neoplasm for which strategies able to regulate cell cycle progression may be useful in clinical treatment. We investigated the antiproliferative effect of NaB on 2 NSCLC cell lines (NCI-H460 and NCI-H23) that differ in their TP53 status.…”

Apoptosis induced by the histone deacetylase inhibitor sodium butyrate in human leukemic lymphoblasts

“…B utyrate in millimolar concentrations has long been known to be an inhibitor of histone deacetylases and to cause reversible G0/G1 growth arrest and induction of differentiation markers in cells from numerous species and tissues (reviewed in refs 1, 2). More recently, butyrate has been recognized to induce apoptosis in certain nontransformed as well as transformed cell types, including colorectal (3, 4), breast (5, 6), hepatic (7), and hematopoietic malignant (8–10) cell lines. Due to its growth‐inhibiting and differentiation‐inducing ability, butyrate as well as its analogs with better pharmacodynamic properties were tested, alone or in combination with other anti‐cancer drugs, in the therapy of solid tumors (11) and leukemias (12–14).…”