The histone deacetylase inhibitor valproic acid alters sensitivity towards all trans retinoic acid in acute myeloblastic leukemia cells.
Acute myeloblastic leukemia (AML) may be classified in a number of ways. Using the French American British classification, the M3 form of the disease or acute promyelocytic leukemia (APL) has been found to be sensitive in vitro and in vivo to the retinoid all trans retinoic acid (ATRA). The mechanism for this is by restoration of normal gene expression through the release of histone deacetylase complexes (HDACs). In contrast to APL, other forms of AML are either nonresponsive or show blunted responses to ATRA. We evaluated if the inhibitor of HDAC activity, valproic acid (VPA), could mimic or enhance retinoid sensitivity in the AML cell line, OCI/AML-2, and clinical samples derived from patients with AML. An Affymetrix GeneChip experiment demonstrated that VPA modulated the expression of numerous genes in OCI/AML-2 cells that were not affected by ATRA including p21, a retinoid responsive gene in APL. VPA induced p21 expression in OCI/AML-2 cells and the majority of the AML samples tested; this was associated with cell cycle arrest and apoptosis not seen with ATRA alone. The addition of ATRA to VPA accentuated many of these responses, supporting the potential beneficial combination of these drugs in the treatment of AML.
Trus
M R
MR
Department of Medical Biophysics, Princess Margaret Hospital/Ontario Cancer Institute University Health Network, Toronto, Ontario, Canada.
Yang
L
L
Suarez Saiz
F
F
Bordeleau
L
L
Jurisica
I
I
Minden
M D
MD
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000494:pharmacology*; D014635:Valproic Acid / Q000494:pharmacology*
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D014212:Tretinoin; D014635:Valproic Acid; D006655:Histone Deacetylases