A Short-Term Trial of Butyrate to Stimulate Fetal-Globin-Gene Expression in the β-Globin Disorders

Perrine, Susan P.; Ginder, Gordon D.; Faller, Douglas V.; Dover, GJ; Ikuta, Takuya; Witkowska, H. Ewa; Cai, Shi‐Ping; Vichinsky, E.; Olivieri, Nancy F.

doi:10.1056/nejm199301143280202

Cited by 432 publications

(287 citation statements)

References 42 publications

Supporting

Mentioning

278

Contrasting

Unclassified

Order By: Relevance

“…The initial clinical findings with compounds such as sodium butyrate (Kruh, 1982;Miller et al, 1987;Perrine et al, 1993) that has a very short half-life in vivo and phenylacetate (Chang et al, 1999), which only produced modest anticancer effects and significant toxicities, were discouraging. Similarly, TSA which is associated with excessive toxicity and is unstable in vivo has limited clinical applicability (Jung, 2001;Hess-Stumpp, 2005).…”

Section: Cellular Effects Of Hdac Inhibitorsmentioning

confidence: 99%

Modulation of cellular radiation responses by histone deacetylase inhibitors

Karagiannis

El‐Osta

2006

Oncogene

View full text Add to dashboard Cite

Histone deacetylase (HDAC) inhibitors are emerging as a new class of targeted cancer chemotherapeutics. Several HDAC inhibitors are currently in clinical trials and promising anticancer effects at well-tolerated doses have been observed for both hematologic and solid cancers. HDAC inhibitors have been shown to induce cell-cycle and growth arrest, differentiation and in certain cases apoptosis in cell cultures and in vivo. However, it is known that these compounds induce varying responses in different cells and biological settings, and identifying their precise mechanisms of action is an area of great interest. Important findings are continually expanding our understanding of the cellular effects of HDAC inhibitors and recent studies will be briefly outlined in this review. In addition to their intrinsic anticancer properties, numerous studies have demonstrated that HDAC inhibitors can modulate cellular responses to other cytotoxic modalities including ionizing radiation, ultraviolet radiation and chemotherapeutic drugs. Hence, there is a growing interest in potential clinical use of HDAC inhibitors in combination with conventional cancer therapies. In this review, the interaction of HDAC inhibitors with other anticancer agents is discussed. The focus of the article is on the different mechanisms by which HDAC inhibitors enhance the sensitivity of cells to the effects of ionizing radiation.

show abstract

Section: Cellular Effects Of Hdac Inhibitorsmentioning

confidence: 99%

Modulation of cellular radiation responses by histone deacetylase inhibitors

Karagiannis

El‐Osta

2006

Oncogene

View full text Add to dashboard Cite

show abstract

“…Arginine butyrate is a butyrate salt which has been utilized in clinical studies of hemoglobinopathies and has been shown to induce globin gene synthesis in vitro and in vivo. 10 We now report that exposure of p 210 bcr-abl overexpressing leukemia cells to concentrations of arginine butyrate known to be physiologically achievable in vivo can induce apoptosis of the cells, and that this effect is concordant with a decrease in p 210 bcr-abl mRNA, protein and abl tyrosine kinase activity.…”

Section: Introductionmentioning

confidence: 66%

“…Butyrate and its derivatives are capable of modulating expression of a number of differentiation genes, including alkaline phosphatase, peptide hormones and the globin genes without affecting viability of normal cells, and it is speculated that these effects may be mediated by histone hyperacetylation, thereby allowing for transcription of inactivated genes. 1,10,29 Butyrates have also been shown to alter cell cycling by inducing a G1 arrest and inhibiting accumulation of late G1-related genes, including p53, thymidine kinase and cdc2. 30 These effects are reversible upon removal of butyrate and therefore are unlikely to contribute to the induction of apoptosis in K562 and in other hematopoietic cell lines.…”

Section: Figurementioning

confidence: 99%

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

Urbano

Foss

1998

Leukemia

View full text Add to dashboard Cite

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.

show abstract

“…Given the promising in vitro and in vivo studies on the stimulation effect of butyrate on HbF synthesis and the low toxicity profile of this drug, in 1993, a pharmaceutically suitable preparation of butyrate, Arginine Butyrate, was administrated in six patients, three with sickle cell disease and three with β-thalassemia [140]. This initial study provided evidence that Arginine Butyrate infusion rapidly increases HbF production up to levels suitable to ameliorate the clinical condition of these β-hemoglobinopathies.…”

Section: Butyratementioning

confidence: 99%