An oral HemokineTM, α-methylhydrocinnamate, enhances myeloid and neutrophil recovery following irradiation in vivo

Douglas V. Faller, Serguei A. Castaneda, Daohong Zhou, Merriline Vedamony, Peter E. Newburger, Gary L. White, Stanley Kosanke, P. Artur Plett, Christie Orschell, Michael S. Boosalis, Susan P. Perrine

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Abstract

An oral therapeutic which reduces duration of cytopenias and is active following accidental radiation exposures is an unmet need in radiation countermeasures. Alpha methylhydrocinnamate (ST7) prolongs STAT-5 phosphorylation, reduces growth-factor dependency of multi-lineage cell lines, and stimulates erythropoiesis. Here, ST7 and its isomers were studied for their effects on myeloid progenitors and hematopoietic stem cells (HSCs) following radiation, in nonhuman primates, and murine irradiation models. Addition of ST7 or ST7-S increased CFU-GM production by 1.7-fold (p < 0.001), reduced neutrophil apoptosis comparable to G-CSF, and enhanced HSC survival post-radiation by 2-fold, (p = 0.028). ST7 and ST7-S administered in normal baboons increased ANC and platelet counts by 50–400%. In sub-lethally-irradiated mice, ANC nadir remained > 200/mm3 and neutropenia recovered in 6 days with ST7 treatment and 18 days in controls (p < 0.05). In lethally-irradiated mice, marrow pathology at 15 days was hypocellular (10% cellularity) in controls, but normal (55–75% cellularity) with complete neutrophil maturation with ST7-S treatment. Following lethal irradiation, ST7, given orally for 4 days, reduced mortality, with 30% survival in ST7-animals vs 8% in controls, (p < 0.05). Collectively, the studies indicate that ST7 and ST7-S enhance myeloid recovery post-radiation and merit further evaluation to accelerate hematologic recovery in conditions of radiation-related and other marrow hypoplasias.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalBlood Cells, Molecules, and Diseases
Volume63
DOIs
StatePublished - Mar 1 2017

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Neutrophils
Radiation
Bone Marrow
Myeloid Progenitor Cells
Granulocyte-Macrophage Progenitor Cells
Erythropoiesis
Hematopoietic Stem Cells
Neutropenia
Primates
Intercellular Signaling Peptides and Proteins
Phosphorylation
Pathology
Cell Line
Mortality
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Hematology
  • Molecular Biology
  • Cell Biology

Cite this

Faller, D. V., Castaneda, S. A., Zhou, D., Vedamony, M., Newburger, P. E., White, G. L., ... Perrine, S. P. (2017). An oral HemokineTM, α-methylhydrocinnamate, enhances myeloid and neutrophil recovery following irradiation in vivo. Blood Cells, Molecules, and Diseases, 63, 1-8. https://doi.org/10.1016/j.bcmd.2016.10.021

An oral HemokineTM, α-methylhydrocinnamate, enhances myeloid and neutrophil recovery following irradiation in vivo. / Faller, Douglas V.; Castaneda, Serguei A.; Zhou, Daohong; Vedamony, Merriline; Newburger, Peter E.; White, Gary L.; Kosanke, Stanley; Plett, P. Artur; Orschell, Christie; Boosalis, Michael S.; Perrine, Susan P.

In: Blood Cells, Molecules, and Diseases, Vol. 63, 01.03.2017, p. 1-8.

Research output: Contribution to journalArticle

Faller, DV, Castaneda, SA, Zhou, D, Vedamony, M, Newburger, PE, White, GL, Kosanke, S, Plett, PA, Orschell, C, Boosalis, MS & Perrine, SP 2017, 'An oral HemokineTM, α-methylhydrocinnamate, enhances myeloid and neutrophil recovery following irradiation in vivo', Blood Cells, Molecules, and Diseases, vol. 63, pp. 1-8. https://doi.org/10.1016/j.bcmd.2016.10.021
Faller, Douglas V. ; Castaneda, Serguei A. ; Zhou, Daohong ; Vedamony, Merriline ; Newburger, Peter E. ; White, Gary L. ; Kosanke, Stanley ; Plett, P. Artur ; Orschell, Christie ; Boosalis, Michael S. ; Perrine, Susan P. / An oral HemokineTM, α-methylhydrocinnamate, enhances myeloid and neutrophil recovery following irradiation in vivo. In: Blood Cells, Molecules, and Diseases. 2017 ; Vol. 63. pp. 1-8.
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abstract = "An oral therapeutic which reduces duration of cytopenias and is active following accidental radiation exposures is an unmet need in radiation countermeasures. Alpha methylhydrocinnamate (ST7) prolongs STAT-5 phosphorylation, reduces growth-factor dependency of multi-lineage cell lines, and stimulates erythropoiesis. Here, ST7 and its isomers were studied for their effects on myeloid progenitors and hematopoietic stem cells (HSCs) following radiation, in nonhuman primates, and murine irradiation models. Addition of ST7 or ST7-S increased CFU-GM production by 1.7-fold (p < 0.001), reduced neutrophil apoptosis comparable to G-CSF, and enhanced HSC survival post-radiation by 2-fold, (p = 0.028). ST7 and ST7-S administered in normal baboons increased ANC and platelet counts by 50–400{\%}. In sub-lethally-irradiated mice, ANC nadir remained > 200/mm3 and neutropenia recovered in 6 days with ST7 treatment and 18 days in controls (p < 0.05). In lethally-irradiated mice, marrow pathology at 15 days was hypocellular (10{\%} cellularity) in controls, but normal (55–75{\%} cellularity) with complete neutrophil maturation with ST7-S treatment. Following lethal irradiation, ST7, given orally for 4 days, reduced mortality, with 30{\%} survival in ST7-animals vs 8{\%} in controls, (p < 0.05). Collectively, the studies indicate that ST7 and ST7-S enhance myeloid recovery post-radiation and merit further evaluation to accelerate hematologic recovery in conditions of radiation-related and other marrow hypoplasias.",
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