Cardiac glycosides suppress the maintenance of stemness and malignancy via inhibiting HIF-1α in human glioma stem cells

Dae Hee Lee, Sang Cheul Oh, Amber J. Giles, Jinkyu Jung, Mark R. Gilbert, Deric M. Park

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Tissue hypoxia contributes to solid tumor pathogenesis by activating a series of adaptive programs. We previously showed that hypoxia promotes the preferential expansion and maintenance of CD133 positive human glioma stem cells (GSC) in a hypoxia inducible factor 1 alpha (HIF-1α)-dependent mechanism. Here, we examined the activity of digitoxin (DT), a cardiac glycoside and a putative inhibitor of HIF- 1α, on human GSC in vitro and in vivo. During hypoxic conditions (1% O2), we observed the effect of DT on the intracellular level of HIF-1α and the extracellular level of vascular endothelial growth factor (VEGF) in human GSC. We found that DT at clinically achievable concentrations, suppressed HIF-1α accumulation during hypoxic conditions in human GSC and established glioma cell lines. DT treatment also significantly attenuated hypoxia-induced expression of VEGF, a downstream target of HIF-1α. Exposure to DT also reduced hypoxia-induced activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. Furthermore, DT potently inhibited neurosphere formation, and decreased CD133 expression even at concentrations that were not overtly cytotoxic. Lastly, treatment with DT reduced GSC engraftment in an in vivo xenograft model of glioblastoma. Intraperitoneal injections of DT significantly inhibited the growth of established glioblastoma xenografts, and suppressed expression of HIF-1α and carbonic anhydrase (CA9), a surrogate marker of hypoxia. Taken together, these results suggest that DT at clinically achievable concentration functions as an inhibitor of HIF-1α, worthy of further investigations in the therapy of glioblastoma.

Original languageEnglish
Pages (from-to)40233-40245
Number of pages13
JournalOncotarget
Volume8
Issue number25
DOIs
Publication statusPublished - 2017

Fingerprint

Digitoxin
Hypoxia-Inducible Factor 1
Cardiac Glycosides
Glioma
Stem Cells
Maintenance
Neoplasms
Glioblastoma
Heterografts
Carbonic Anhydrases
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Intraperitoneal Injections
Vascular Endothelial Growth Factor A
Therapeutics
Biomarkers
Hypoxia
Cell Line

Keywords

  • Cancer stem cell
  • Cardiac glycoside
  • Digitoxin
  • HIF
  • Hypoxia

ASJC Scopus subject areas

  • Oncology

Cite this

Cardiac glycosides suppress the maintenance of stemness and malignancy via inhibiting HIF-1α in human glioma stem cells. / Lee, Dae Hee; Oh, Sang Cheul; Giles, Amber J.; Jung, Jinkyu; Gilbert, Mark R.; Park, Deric M.

In: Oncotarget, Vol. 8, No. 25, 2017, p. 40233-40245.

Research output: Contribution to journalArticle

Lee, Dae Hee ; Oh, Sang Cheul ; Giles, Amber J. ; Jung, Jinkyu ; Gilbert, Mark R. ; Park, Deric M. / Cardiac glycosides suppress the maintenance of stemness and malignancy via inhibiting HIF-1α in human glioma stem cells. In: Oncotarget. 2017 ; Vol. 8, No. 25. pp. 40233-40245.
@article{113ff8e4a1e4468cb2ddb3ffa2280e65,
title = "Cardiac glycosides suppress the maintenance of stemness and malignancy via inhibiting HIF-1α in human glioma stem cells",
abstract = "Tissue hypoxia contributes to solid tumor pathogenesis by activating a series of adaptive programs. We previously showed that hypoxia promotes the preferential expansion and maintenance of CD133 positive human glioma stem cells (GSC) in a hypoxia inducible factor 1 alpha (HIF-1α)-dependent mechanism. Here, we examined the activity of digitoxin (DT), a cardiac glycoside and a putative inhibitor of HIF- 1α, on human GSC in vitro and in vivo. During hypoxic conditions (1{\%} O2), we observed the effect of DT on the intracellular level of HIF-1α and the extracellular level of vascular endothelial growth factor (VEGF) in human GSC. We found that DT at clinically achievable concentrations, suppressed HIF-1α accumulation during hypoxic conditions in human GSC and established glioma cell lines. DT treatment also significantly attenuated hypoxia-induced expression of VEGF, a downstream target of HIF-1α. Exposure to DT also reduced hypoxia-induced activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. Furthermore, DT potently inhibited neurosphere formation, and decreased CD133 expression even at concentrations that were not overtly cytotoxic. Lastly, treatment with DT reduced GSC engraftment in an in vivo xenograft model of glioblastoma. Intraperitoneal injections of DT significantly inhibited the growth of established glioblastoma xenografts, and suppressed expression of HIF-1α and carbonic anhydrase (CA9), a surrogate marker of hypoxia. Taken together, these results suggest that DT at clinically achievable concentration functions as an inhibitor of HIF-1α, worthy of further investigations in the therapy of glioblastoma.",
keywords = "Cancer stem cell, Cardiac glycoside, Digitoxin, HIF, Hypoxia",
author = "Lee, {Dae Hee} and Oh, {Sang Cheul} and Giles, {Amber J.} and Jinkyu Jung and Gilbert, {Mark R.} and Park, {Deric M.}",
year = "2017",
doi = "10.18632/oncotarget.16714",
language = "English",
volume = "8",
pages = "40233--40245",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "25",

}

TY - JOUR

T1 - Cardiac glycosides suppress the maintenance of stemness and malignancy via inhibiting HIF-1α in human glioma stem cells

AU - Lee, Dae Hee

AU - Oh, Sang Cheul

AU - Giles, Amber J.

AU - Jung, Jinkyu

AU - Gilbert, Mark R.

AU - Park, Deric M.

PY - 2017

Y1 - 2017

N2 - Tissue hypoxia contributes to solid tumor pathogenesis by activating a series of adaptive programs. We previously showed that hypoxia promotes the preferential expansion and maintenance of CD133 positive human glioma stem cells (GSC) in a hypoxia inducible factor 1 alpha (HIF-1α)-dependent mechanism. Here, we examined the activity of digitoxin (DT), a cardiac glycoside and a putative inhibitor of HIF- 1α, on human GSC in vitro and in vivo. During hypoxic conditions (1% O2), we observed the effect of DT on the intracellular level of HIF-1α and the extracellular level of vascular endothelial growth factor (VEGF) in human GSC. We found that DT at clinically achievable concentrations, suppressed HIF-1α accumulation during hypoxic conditions in human GSC and established glioma cell lines. DT treatment also significantly attenuated hypoxia-induced expression of VEGF, a downstream target of HIF-1α. Exposure to DT also reduced hypoxia-induced activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. Furthermore, DT potently inhibited neurosphere formation, and decreased CD133 expression even at concentrations that were not overtly cytotoxic. Lastly, treatment with DT reduced GSC engraftment in an in vivo xenograft model of glioblastoma. Intraperitoneal injections of DT significantly inhibited the growth of established glioblastoma xenografts, and suppressed expression of HIF-1α and carbonic anhydrase (CA9), a surrogate marker of hypoxia. Taken together, these results suggest that DT at clinically achievable concentration functions as an inhibitor of HIF-1α, worthy of further investigations in the therapy of glioblastoma.

AB - Tissue hypoxia contributes to solid tumor pathogenesis by activating a series of adaptive programs. We previously showed that hypoxia promotes the preferential expansion and maintenance of CD133 positive human glioma stem cells (GSC) in a hypoxia inducible factor 1 alpha (HIF-1α)-dependent mechanism. Here, we examined the activity of digitoxin (DT), a cardiac glycoside and a putative inhibitor of HIF- 1α, on human GSC in vitro and in vivo. During hypoxic conditions (1% O2), we observed the effect of DT on the intracellular level of HIF-1α and the extracellular level of vascular endothelial growth factor (VEGF) in human GSC. We found that DT at clinically achievable concentrations, suppressed HIF-1α accumulation during hypoxic conditions in human GSC and established glioma cell lines. DT treatment also significantly attenuated hypoxia-induced expression of VEGF, a downstream target of HIF-1α. Exposure to DT also reduced hypoxia-induced activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway. Furthermore, DT potently inhibited neurosphere formation, and decreased CD133 expression even at concentrations that were not overtly cytotoxic. Lastly, treatment with DT reduced GSC engraftment in an in vivo xenograft model of glioblastoma. Intraperitoneal injections of DT significantly inhibited the growth of established glioblastoma xenografts, and suppressed expression of HIF-1α and carbonic anhydrase (CA9), a surrogate marker of hypoxia. Taken together, these results suggest that DT at clinically achievable concentration functions as an inhibitor of HIF-1α, worthy of further investigations in the therapy of glioblastoma.

KW - Cancer stem cell

KW - Cardiac glycoside

KW - Digitoxin

KW - HIF

KW - Hypoxia

UR - http://www.scopus.com/inward/record.url?scp=85021029627&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85021029627&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.16714

DO - 10.18632/oncotarget.16714

M3 - Article

AN - SCOPUS:85021029627

VL - 8

SP - 40233

EP - 40245

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 25

ER -