The pan-caspase inhibitor Q-VD-OPh has anti-leukemia effects and can interact with vitamin D analogs to increase HPK1 signaling in AML cells

Leuk Res. 2012 Jul;36(7):884-8. doi: 10.1016/j.leukres.2012.03.023. Epub 2012 Apr 26.

Abstract

Caspase function is known to be essential for cell death by apoptosis, but it is now increasingly recognized that these proteases also play important roles in other cellular events. Here we report for the first time that inhibition of cellular caspase activity can induce differentiation of AML blasts, and can enhance vitamin D-induced cell differentiation of these cells. This was studied in blasts obtained from nine patients with AML and one patient with CML by ex vivo culture in the presence of Q-VD-OPh (QVD), a pan caspase inhibitor. Cell differentiation was manifested by the expression of markers of monocytic differentiation CD11b and CD14. Differentiation induced by 1α,25-dihydroxyvitamin D3 (1,25D) or its analogs PRI-1906 and PRI-2191 was enhanced by QVD to a varying degree, depending on the subtype of the leukemia. QVD and 1,25D-induced differentiation was accompanied by increased signaling by Hematopoietic Progenitor Kinase 1(HPK1), and the expression of transcription factors known to be involved in monocytic differentiation was increased. Although the magnitude and nature of these changes were not invariable, it is clear that caspase inhibitors warrant attention as components of differentiation therapy of leukemia, perhaps in combination with derivatives of vitamin D.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Amino Acid Chloromethyl Ketones / administration & dosage
  • Amino Acid Chloromethyl Ketones / pharmacology*
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology*
  • Caspase Inhibitors
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cohort Studies
  • Cysteine Proteinase Inhibitors / administration & dosage
  • Cysteine Proteinase Inhibitors / pharmacology
  • Drug Evaluation, Preclinical
  • Drug Interactions
  • Female
  • Gene Expression Regulation, Leukemic / drug effects
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology*
  • Male
  • Middle Aged
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / physiology
  • Quinolines / administration & dosage
  • Quinolines / pharmacology*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Tumor Cells, Cultured
  • Up-Regulation / drug effects
  • Vitamin D / administration & dosage
  • Vitamin D / analogs & derivatives
  • Vitamin D / pharmacology*

Substances

  • Amino Acid Chloromethyl Ketones
  • Antineoplastic Agents
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • Quinolines
  • quinoline-val-asp(OMe)-CH2-OPH
  • Vitamin D
  • hematopoietic progenitor kinase 1
  • Protein-Serine-Threonine Kinases