HIV-1 protease inhibitor ritonavir potentiates the effect of 1,25-dihydroxyvitamin D3 to induce growth arrest and differentiation of human myeloid leukemia cells via down-regulation of CYP24

Leuk Res. 2006 Aug;30(8):1005-11. doi: 10.1016/j.leukres.2005.12.008. Epub 2006 Feb 7.

Abstract

HIV-1 protease inhibitor, ritonavir (RTV) is a potent inhibitor of cytochrome p450 (CYPs) enzymes. This study explored the effects of RTV on CYP24 which converts 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] to its inactive form 1,24,25,(OH)(3). Real-time RT-PCR showed that exposure of HL-60 cells to 1,25(OH)(2)D(3) induced expression of CYP24, and pre-incubation of these cells with RTV decreased this transcripts, resulting in increased intracellular levels of 1,25(OH)(2)D(3) and potentiation of the ability of 1,25(OH)(2)D(3) to induce growth arrest and differentiation of these cells. Taken together, inhibition of CYP24 might open a new paradigm for therapy using Vitamin D compounds.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Calcitriol / pharmacology*
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Down-Regulation / drug effects
  • Drug Synergism
  • Gene Expression Profiling
  • Gene Expression Regulation, Enzymologic / drug effects
  • HIV Protease Inhibitors / pharmacology
  • HL-60 Cells
  • Humans
  • Leukemia, Myeloid / drug therapy*
  • Leukemia, Myeloid / metabolism
  • Lipopolysaccharide Receptors / biosynthesis
  • Lipopolysaccharide Receptors / drug effects
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Ritonavir / pharmacology*
  • Steroid Hydroxylases / antagonists & inhibitors*
  • Steroid Hydroxylases / genetics
  • Steroid Hydroxylases / metabolism
  • Structure-Activity Relationship
  • Superoxides / metabolism
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / genetics
  • Vitamin D3 24-Hydroxylase

Substances

  • HIV Protease Inhibitors
  • Lipopolysaccharide Receptors
  • Superoxides
  • Steroid Hydroxylases
  • Vitamin D3 24-Hydroxylase
  • Calcitriol
  • Ritonavir