Butyrate‐stable monosaccharide derivatives induce maturation and apoptosis in human acute myeloid leukaemia cells

Santini, Valeria; Scappini, Barbara; Gozzini, Antonella; Grossi, Alberto; Villa, Pierre; Ronco, G.; Douillet, Olivier; Pouillart, P.; Bernabei, Pietro Antonio; Pr, Ferrini

doi:10.1046/j.1365-2141.1998.00727.x

Cited by 22 publications

(12 citation statements)

References 32 publications

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“…In fact, although butyrate arrests normal cells in G 1 , it induces apoptosis in transformed cells within 4 hours after G 1 -S arrest. 58,[65][66][67][68][69][70][71][72][73][74][75][76][77] Thus, the activities of butyrate that cause cell cycle arrest may be problematic when the drug is used in patients with hemoglobinopathies unless it is given intermittently, which, in turn, limits the amount of ␥-globin and the proportions of F cells that can be induced.…”

Section: Discussionmentioning

confidence: 99%

Short-chain fatty acid derivatives stimulate cell proliferation and induce STAT-5 activation

Boosalis

Bandyopadhyay

Bresnick

et al. 2001

Blood

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Current chemotherapeutic and butyrate therapeutics that induce fetal hemoglobin expression generally also suppress erythropoiesis, limiting the production of cells containing fetal hemoglobin (F cells). Recently, selected short-chain fatty acid derivatives (SCFADs) were identified that induce endogenous ␥-globin expression in K562 cells and human burst-forming units-erythroid and that increase proliferation of human erythroid progenitors and a multilineage interleukin-3-dependent hematopoietic cell line. In this report, ␥-globin inducibility by these SCFADs was further demonstrated in mice transgenic for the locus control region and the entire ␤-globin gene locus in a yeast artificial chromosome and in 2 globin promoter-reporter assays. Conditioned media experiments strongly suggest that their proliferative activity is a direct effect of the test compounds. Investigation of potential mechanisms of action of these SCFADs demonstrates that these compounds induce prolonged expression of the growth-promoting genes c-myb and c-myc. Both butyrate and specific growth-stimulatory SCFADs induced prolonged signal transducer and activator of transcription (STAT)-5 phosphorylation and activation, and c-cis expression, persisting for more than 120 minutes, whereas with IL-3 alone phosphorylation disappeared within minutes. In contrast to butyrate treatment, the growth-stimulating SCFADs did not result in bulk histone H4 hyperacetylation or induction of p21 Waf/Cip , which mediates the suppression of cellular growth by butyrate. These findings suggest that the absence of bulk histone hyperacetylation and p21 induction, but prolonged induction of cis, myb, myc, and IntroductionButyrate analogs have been of interest as potential therapeutics for the ␤-globin disorders following the demonstration that butyrate could transcriptionally activate developmentally silenced fetal and embryonic globin genes in many experimental conditions. [1][2][3][4][5][6][7][8][9][10][11] In clinical trials, arginine butyrate stimulated hemoglobin F (HbF) synthesis to levels above 20% and induced a nearly 2-fold increase in the amount of HbF/cell and in proportions of red blood cells expressing HbF (F reticulocytes) in patients with sickle cell anemia. [10][11][12] With constant use, however, the activity of the drug in maintaining substantial increases in HbF-containing erythrocytes gradually decreased. 13 We hypothesized that this tachyphylaxis was due to the coincident cellular growth-inhibitory properties of butyrate and developed intermittent or "pulse" regimens (4 days of use per month) to surmount this problem. 12 Although this regimen proved effective, it also imposed severe limitations on the amount of drug that can be delivered to the patient. An orally bioavailable transcriptional inducer of ␥-globin that does not have cellular growth-inhibitory properties and could be administered more frequently to stimulate a further increase in the proportion of HbF-containing cells (F cells) would be therapeutically advantageous for ␤-globin disord...

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Section: Discussionmentioning

confidence: 99%

Short-chain fatty acid derivatives stimulate cell proliferation and induce STAT-5 activation

Boosalis

Bandyopadhyay

Bresnick

et al. 2001

Blood

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“…These effects show no correlation with previous signs of differentiation (i.e., FAB classification). Butyrates are another group of drugs that seem to induce gene expression via histone hyperacetylation, and monosaccharide butyrate derivatives can also induce differentiation in native AML blasts for a subset of patients [41].…”

Section: Altered Histone Acetylationmentioning

confidence: 99%

New Strategies for the Treatment of Acute Myelogenous Leukemia: Differentiation Induction—Present Use and Future Possibilities

Bruserud

Gjertsen

2000

STEM CELLS

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should be regarded as a promising therapeutic approach, especially as a part of immunotherapy or in combination with intensive chemotherapy to increase the susceptibility of AML blasts to drug-induced apoptosis. Although the morphology-based French-American-British classification was used to identify APL as an AML subset that required a special treatment, it seems unlikely that this classification alone can be used to identify new subsets of AML patients with special therapeutic requirements. Future studies on differentiation induction in AML should therefore focus on A) the identification of therapeutic agents with more predictable effects; B) the use of clinical and laboratory parameters to define new subsets of AML patients in which differentiation induction has a predictable and beneficial effect, and C) the characterization of how AML blast sensitivity to drug-induced apoptosis is altered by differentiation induction.

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“…6 Other monosaccharide prodrugs of butyrate have demonstrated similar ability to induce apoptosis of fresh myeloid leukemia cells. 19 A high concentration of butyrate (5 mM) has also been shown to induce apoptosis accompanied by an increase in the level of hsp 70 protein expression in the Burkitt lymphoma cell line BL-30 after 16 h of exposure. 7 Of interest, butyrate-induced apoptosis in HL60 cells was correlated with decrease in bcl-2 protein expression, suggesting that one mechanism for the butyrate-mediated effects observed in leukemia cells may be related to effects of butyrate on expression or function of anti-apoptosis genes.…”

Section: Figurementioning

confidence: 99%

“…Recently Santini et al 19 reported that the butyrate monosaccharide ester, MAG=3 induced apoptosis in HL60 cells without overexpression of the known apoptotic regulatory genes, c-myc and p53, but with decrease in bcl-2 expression. Perhaps the induction of apoptosis in HL60, K562, and other cell lines expressing anti-apoptosis genes represents a selective sensitivity of these cells to the effects of butyrates to modulate expression of genes important in cellular homeostasis.…”

Section: Figurementioning

confidence: 99%

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

Urbano

Foss

1998

Leukemia

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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.

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Butyrate‐stable monosaccharide derivatives induce maturation and apoptosis in human acute myeloid leukaemia cells

Cited by 22 publications

References 32 publications

Short-chain fatty acid derivatives stimulate cell proliferation and induce STAT-5 activation

Short-chain fatty acid derivatives stimulate cell proliferation and induce STAT-5 activation

New Strategies for the Treatment of Acute Myelogenous Leukemia: Differentiation Induction—Present Use and Future Possibilities

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

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