Expression of 11beta-hydroxysteroid dehydrogenase 2 contributes to glucocorticoid resistance in lymphoblastic leukemia cells

Leuk Res. 2011 Dec;35(12):1644-8. doi: 10.1016/j.leukres.2011.07.002. Epub 2011 Jul 26.

Abstract

Synthetic glucocorticoids (GCs) form a crucial first-line treatment for childhood acute lymphoblastic leukemia (ALL). However prolonged GC therapy frequently leads to GC-resistance with an unclear molecular mechanism. 11β-hydroxysteroid dehydrogenase (11β-HSD) 2 inactivates GCs within cells. Here, we show the association between GC sensitivity and 11β-HSD2 expression in human T-cell leukemic cell lines. 11β-HSD2 mRNA and protein levels were considerably higher in GC-resistant MOLT4F cells than in GC-sensitive CCRF-CEM cells. The 11β-HSD inhibitor, carbenoxolone pre-treatment resulted in greater cell death with prednisolone assessed by methyl-thiazol-tetrazolium assay and caspase-3/7 assay, suggesting that 11β-HSD2 is a cause of GC-resistance in ALL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 2 / antagonists & inhibitors
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2 / genetics*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2 / metabolism
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Cell Line, Tumor
  • Dexamethasone / administration & dosage
  • Dexamethasone / pharmacology
  • Drug Evaluation, Preclinical
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Drug Synergism
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / physiology
  • Gene Expression Regulation, Leukemic / drug effects
  • Gene Expression Regulation, Leukemic / physiology
  • Glucocorticoids / therapeutic use*
  • Humans
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Prednisolone / administration & dosage
  • Prednisolone / pharmacology
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism

Substances

  • Antineoplastic Agents, Hormonal
  • Enzyme Inhibitors
  • Glucocorticoids
  • Receptors, Glucocorticoid
  • glucocorticoid receptor alpha
  • Dexamethasone
  • Prednisolone
  • 11-beta-Hydroxysteroid Dehydrogenase Type 2