Ex vivo zidovudine (AZT) treatment of CD34+ bone marrow progenitors causes decreased steady state mitochondrial DNA (mtDNA) and increased lactate production

Lionel D. Lewis, S. Amin, C. I. Civin, P. S. Lietman

Research output: Contribution to journalArticle

Abstract

Haematopoietic suppression is one of the dose-limiting side effects of chronic zidovudine (AZT) therapy. We tested the hypothesis that AZT would reduce mitochondrial DNA (mtDNA) content in haematopoietic progenitors causing impaired haematopoiesis and mitochondrial dysfunction. We studied the effects of AZT 0-50 μM in vitro, on normal human CD34+ haematopoietic progenitor cells cultured ex vivo for up to 12 days. The mean AZT IC50 for granulocyte (phenotype CD15+/CD14-) and erythroid (phenotype glycophorin+/CD45 -) cell proliferation was 2.5 μM (SD ± 0.7) and 0.023 μM (SD ± 0.005), respectively. In myeloid-rich cell cultures, the mean lactate content of the media, compared to untreated controls, increased by 86% (SD ± 23) at 10 μM AZT and in erythroid-rich cultures it increased by 134% (SD ± 24) in the presence of 0.5 μM AZT. In myeloid-rich cultures the AZT IC50 for the reduction in the mitochondrial/nuclear DNA content ratio was 5.6 μM, whereas in erythroid rich cultures this AZT IC50 was <0.0005 μM. AZT produced concentration-dependent inhibition of CD34+ progenitor proliferation into both myeloid and erythroid lineages; erythropoiesis was more sensitive than myelopoiesis. Concurrently, AZT reduced steady state mtDNA content, while increasing lactate production. These findings support the hypothesis that mtDNA is one of the intracellular targets involved in the pathogenesis of AZT-associated bone marrow progenitor cell toxicity.

Original languageEnglish (US)
Pages (from-to)173-185
Number of pages13
JournalHuman and Experimental Toxicology
Volume23
Issue number4
DOIs
StatePublished - Apr 2004

Fingerprint

Zidovudine
Mitochondrial DNA
Lactic Acid
Bone
Bone Marrow
Inhibitory Concentration 50
Glycophorin
Cell proliferation
Myelopoiesis
Phenotype
Cell culture
Toxicity
Erythropoiesis
Hematopoiesis
Myeloid Cells
Hematopoietic Stem Cells
Granulocytes
Bone Marrow Cells
Stem Cells
Cell Culture Techniques

Keywords

  • AZT
  • Haematopoietic toxicity
  • Mitochondrial DNA

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Ex vivo zidovudine (AZT) treatment of CD34+ bone marrow progenitors causes decreased steady state mitochondrial DNA (mtDNA) and increased lactate production. / Lewis, Lionel D.; Amin, S.; Civin, C. I.; Lietman, P. S.

In: Human and Experimental Toxicology, Vol. 23, No. 4, 04.2004, p. 173-185.

Research output: Contribution to journalArticle

@article{94cd4e88cee0402b85486cfced669eb8,
title = "Ex vivo zidovudine (AZT) treatment of CD34+ bone marrow progenitors causes decreased steady state mitochondrial DNA (mtDNA) and increased lactate production",
abstract = "Haematopoietic suppression is one of the dose-limiting side effects of chronic zidovudine (AZT) therapy. We tested the hypothesis that AZT would reduce mitochondrial DNA (mtDNA) content in haematopoietic progenitors causing impaired haematopoiesis and mitochondrial dysfunction. We studied the effects of AZT 0-50 μM in vitro, on normal human CD34+ haematopoietic progenitor cells cultured ex vivo for up to 12 days. The mean AZT IC50 for granulocyte (phenotype CD15+/CD14-) and erythroid (phenotype glycophorin+/CD45 -) cell proliferation was 2.5 μM (SD ± 0.7) and 0.023 μM (SD ± 0.005), respectively. In myeloid-rich cell cultures, the mean lactate content of the media, compared to untreated controls, increased by 86{\%} (SD ± 23) at 10 μM AZT and in erythroid-rich cultures it increased by 134{\%} (SD ± 24) in the presence of 0.5 μM AZT. In myeloid-rich cultures the AZT IC50 for the reduction in the mitochondrial/nuclear DNA content ratio was 5.6 μM, whereas in erythroid rich cultures this AZT IC50 was <0.0005 μM. AZT produced concentration-dependent inhibition of CD34+ progenitor proliferation into both myeloid and erythroid lineages; erythropoiesis was more sensitive than myelopoiesis. Concurrently, AZT reduced steady state mtDNA content, while increasing lactate production. These findings support the hypothesis that mtDNA is one of the intracellular targets involved in the pathogenesis of AZT-associated bone marrow progenitor cell toxicity.",
keywords = "AZT, Haematopoietic toxicity, Mitochondrial DNA",
author = "Lewis, {Lionel D.} and S. Amin and Civin, {C. I.} and Lietman, {P. S.}",
year = "2004",
month = "4",
doi = "10.1191/0960327104ht437oa",
language = "English (US)",
volume = "23",
pages = "173--185",
journal = "Human and Experimental Toxicology",
issn = "0960-3271",
publisher = "SAGE Publications Inc.",
number = "4",

}

TY - JOUR

T1 - Ex vivo zidovudine (AZT) treatment of CD34+ bone marrow progenitors causes decreased steady state mitochondrial DNA (mtDNA) and increased lactate production

AU - Lewis, Lionel D.

AU - Amin, S.

AU - Civin, C. I.

AU - Lietman, P. S.

PY - 2004/4

Y1 - 2004/4

N2 - Haematopoietic suppression is one of the dose-limiting side effects of chronic zidovudine (AZT) therapy. We tested the hypothesis that AZT would reduce mitochondrial DNA (mtDNA) content in haematopoietic progenitors causing impaired haematopoiesis and mitochondrial dysfunction. We studied the effects of AZT 0-50 μM in vitro, on normal human CD34+ haematopoietic progenitor cells cultured ex vivo for up to 12 days. The mean AZT IC50 for granulocyte (phenotype CD15+/CD14-) and erythroid (phenotype glycophorin+/CD45 -) cell proliferation was 2.5 μM (SD ± 0.7) and 0.023 μM (SD ± 0.005), respectively. In myeloid-rich cell cultures, the mean lactate content of the media, compared to untreated controls, increased by 86% (SD ± 23) at 10 μM AZT and in erythroid-rich cultures it increased by 134% (SD ± 24) in the presence of 0.5 μM AZT. In myeloid-rich cultures the AZT IC50 for the reduction in the mitochondrial/nuclear DNA content ratio was 5.6 μM, whereas in erythroid rich cultures this AZT IC50 was <0.0005 μM. AZT produced concentration-dependent inhibition of CD34+ progenitor proliferation into both myeloid and erythroid lineages; erythropoiesis was more sensitive than myelopoiesis. Concurrently, AZT reduced steady state mtDNA content, while increasing lactate production. These findings support the hypothesis that mtDNA is one of the intracellular targets involved in the pathogenesis of AZT-associated bone marrow progenitor cell toxicity.

AB - Haematopoietic suppression is one of the dose-limiting side effects of chronic zidovudine (AZT) therapy. We tested the hypothesis that AZT would reduce mitochondrial DNA (mtDNA) content in haematopoietic progenitors causing impaired haematopoiesis and mitochondrial dysfunction. We studied the effects of AZT 0-50 μM in vitro, on normal human CD34+ haematopoietic progenitor cells cultured ex vivo for up to 12 days. The mean AZT IC50 for granulocyte (phenotype CD15+/CD14-) and erythroid (phenotype glycophorin+/CD45 -) cell proliferation was 2.5 μM (SD ± 0.7) and 0.023 μM (SD ± 0.005), respectively. In myeloid-rich cell cultures, the mean lactate content of the media, compared to untreated controls, increased by 86% (SD ± 23) at 10 μM AZT and in erythroid-rich cultures it increased by 134% (SD ± 24) in the presence of 0.5 μM AZT. In myeloid-rich cultures the AZT IC50 for the reduction in the mitochondrial/nuclear DNA content ratio was 5.6 μM, whereas in erythroid rich cultures this AZT IC50 was <0.0005 μM. AZT produced concentration-dependent inhibition of CD34+ progenitor proliferation into both myeloid and erythroid lineages; erythropoiesis was more sensitive than myelopoiesis. Concurrently, AZT reduced steady state mtDNA content, while increasing lactate production. These findings support the hypothesis that mtDNA is one of the intracellular targets involved in the pathogenesis of AZT-associated bone marrow progenitor cell toxicity.

KW - AZT

KW - Haematopoietic toxicity

KW - Mitochondrial DNA

UR - http://www.scopus.com/inward/record.url?scp=2342607034&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=2342607034&partnerID=8YFLogxK

U2 - 10.1191/0960327104ht437oa

DO - 10.1191/0960327104ht437oa

M3 - Article

C2 - 15171568

AN - SCOPUS:2342607034

VL - 23

SP - 173

EP - 185

JO - Human and Experimental Toxicology

JF - Human and Experimental Toxicology

SN - 0960-3271

IS - 4

ER -