Valproic acid inhibits proliferation and induces apoptosis in acute myeloid leukemia cells expressing P-gp and MRP1

Leukemia. 2004 Jul;18(7):1246-51. doi: 10.1038/sj.leu.2403390.


The multidrug resistance (MDR) phenotype, induced by the overexpression of several ABC transporters or by antiapoptotic mechanisms, has been identified as the major cause of drug resistance in the treatment of patients with acute myeloid leukemia (AML). In this study, we have shown that valproic acid (VPA) (a histone deacetylase inhibitor) can inhibit the proliferation of both P-glycoprotein (P-gp)- and MDR-associated protein 1 (MRP1)-positive and -negative cells. VPA also induced apoptosis of P-gp-positive cells. VPA induced apoptosis in K562 cells led to decrease in Flip (FLICE/caspase-8 inhibitory protein) expression with Flip cleavage, which could not be observed in HL60 cells. In HL60/MRP cell line, which proved to be resistant to apoptosis by VPA, we observed an abnormal expression of apoptotic regulatory proteins, overexpression of Bcl-2 and absence of Bax. Also, the Bcl-2 antagonist HA14-1 rapidly restored apoptosis in this cell line. Cotreatment with cytosine arabinoside induced very strong apoptosis in both K562/DOX and HL60/DNR cell lines. VPA also induced apoptosis in AML patient cells expressing P-gp and/or MRP1. Our findings show VPA as an interesting drug that should be tested in clinical trials for overcoming the MDR phenotype in AML patients.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / analysis*
  • Acute Disease
  • Apoptosis / drug effects*
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins / metabolism
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Cytarabine / pharmacology
  • Drug Evaluation, Preclinical
  • Drug Resistance, Multiple / drug effects
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Leukemia, Myeloid / drug therapy*
  • Leukemia, Myeloid / metabolism
  • Leukemia, Myeloid / pathology
  • Multidrug Resistance-Associated Proteins / analysis*
  • Tumor Cells, Cultured
  • Valproic Acid / pharmacology*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • CFLAR protein, human
  • Carrier Proteins
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Multidrug Resistance-Associated Proteins
  • Cytarabine
  • Valproic Acid
  • multidrug resistance-associated protein 1