Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells

KangAe Lee, Zheng (David) Qian, Sergio Rey, Hong Wei, Jun O. Liu, Gregg L. Semenza

Research output: Contribution to journalArticle

207 Citations (Scopus)

Abstract

Using a cell-based reporter gene assay, we screened a library of drugs in clinical use and identified the anthracycline chemotherapeutic agents doxorubicin and daunorubicin as potent inhibitors of hypoxia-inducible factor 1 (HIF-1)-mediated gene transcription. These drugs inhibited HIF-1 by blocking its binding to DNA. Daily administration of doxorubicin or daunorubicin potently inhibited the transcription of a HIF-1-dependent reporter gene as well as endogenous HIF-1 target genes encoding vascular endothelial growth factor, stromal-derived factor 1, and stem cell factor in tumor xenografts. CXCR4 +/sca1+, VEGFR2+/CD34+, and VEGFR2+/CD117+ bone-marrow derived cells were increased in the peripheral blood of SCID mice bearing prostate cancer xenografts but not in tumor-bearing mice treated for 5 days with doxorubicin or daunorubicin, which dramatically reduced tumor vascularization. These results provide a molecular basis for the antiangiogenic effect of anthracycline therapy and have important implications for refining the use of these drugs to treat human cancer more effectively.

Original languageEnglish (US)
Pages (from-to)2353-2358
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number7
DOIs
StatePublished - Feb 17 2009
Externally publishedYes

Fingerprint

Hypoxia-Inducible Factor 1
Anthracyclines
Daunorubicin
Doxorubicin
Drug Therapy
Reporter Genes
Heterografts
Neoplasms
Pharmaceutical Preparations
Stem Cell Factor
SCID Mice
Bone Marrow Cells
Vascular Endothelial Growth Factor A
Genes
Prostatic Neoplasms
DNA
Therapeutics

Keywords

  • Adriamycin
  • Endothelial progenitor cells
  • Hepatocellular carcinoma
  • Hypoxia
  • Xenograft

ASJC Scopus subject areas

  • General

Cite this

Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. / Lee, KangAe; Qian, Zheng (David); Rey, Sergio; Wei, Hong; Liu, Jun O.; Semenza, Gregg L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 7, 17.02.2009, p. 2353-2358.

Research output: Contribution to journalArticle

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AU - Semenza, Gregg L.

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