Enhancement of caffeic acid phenethyl ester on all-trans retinoic acid-induced differentiation in human leukemia HL-60 cells

Toxicol Appl Pharmacol. 2006 Oct 1;216(1):80-8. doi: 10.1016/j.taap.2006.04.007.


All-trans retinoic acid (ATRA) induces complete remission in a high proportion of patients with acute promyelocytic leukemia (APL); however, the response is sometimes very slow. Furthermore, relapse and resistance to treatment often occur despite continued treatment with ATRA. Thereafter, combination treatment strategies have been suggested to circumvent these problems. The present study demonstrates that caffeic acid phenethyl ester (CAPE), a major component of honeybee propolis, enhanced ATRA-induced granulocytic differentiation in HL-60, a human promyelocytic cell line. The differentiation was assessed by Wright-Giemsa stain, nitroblue tetrazolium reduction, and membrane differentiation marker CD11b. In addition, CAPE enhanced ATRA-induced cell cycle arrest at the G1 phase by decreasing the association of cdk2-cyclin E complex. Finally, it was demonstrated that CAPE promoted the ATRA-mediated nuclear transcription activation of RARalpha assessed by EMSA assay and enhanced the expression of target genes including RARalpha, C/EBPepsilon, and p21 protein resulting in the differentiation development of leukemia. It is suggested that CAPE possesses the potential to enhance the efficiency of ATRA in the differentiation therapy of APL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Blotting, Western
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • CD11b Antigen / biosynthesis
  • Caffeic Acids / pharmacology*
  • Cell Cycle / drug effects
  • Cell Differentiation / drug effects*
  • Cell Differentiation / genetics
  • Cyclin E / antagonists & inhibitors
  • Cyclin E / metabolism
  • Cyclin-Dependent Kinase 2 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic / drug effects
  • HL-60 Cells
  • Humans
  • Lipopolysaccharide Receptors / biosynthesis
  • Phenylethyl Alcohol / analogs & derivatives*
  • Phenylethyl Alcohol / pharmacology
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptor alpha / genetics
  • Retinoid X Receptor alpha / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tretinoin / pharmacology*


  • Antineoplastic Agents
  • CCAAT-Enhancer-Binding Proteins
  • CD11b Antigen
  • Caffeic Acids
  • Cyclin E
  • Cyclin-Dependent Kinase Inhibitor p21
  • Lipopolysaccharide Receptors
  • RARA protein, human
  • Receptors, Retinoic Acid
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Retinoic Acid Receptor alpha
  • Retinoid X Receptor alpha
  • CEBPE protein, human
  • Tretinoin
  • Cyclin-Dependent Kinase 2
  • caffeic acid phenethyl ester
  • Phenylethyl Alcohol