TY - JOUR
T1 - Peroxisome proliferator-activated receptor γ agonists potentiate the cytotoxic effect of valproic acid in multiple myeloma cells
AU - Aouali, Nassera
AU - Palissot, Valérie
AU - El-Khoury, Victoria
AU - Moussay, Etienne
AU - Janji, Bassam
AU - Pierson, Sandrine
AU - Brons, Nicolaas H.C.
AU - Kellner, Laurent
AU - Bosseler, Manon
AU - Van Moer, Kris
AU - Berchem, Guy
PY - 2009/12
Y1 - 2009/12
N2 - The main challenge in using chemotherapy to treat multiple myeloma (MM) is drug resistance. In order to evaluate the anti-neoplastic properties of a new drug combination in MM, two clinically available drugs, valproic acid (VPA) a histone deacetylase (HDAC) inhibitor and pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, were tested in vitro on MM cell lines and MM patient cells. The sensitivity towards VPA alone was observed on several MM cell lines tested and also on primary myeloma cells and peripheral blood mononuclear cells from healthy donors. Importantly, the addition of a PPARγ agonist to the VPA treatment increased the cytotoxic effect of VPA in a synergistic/additive manner on the different MM cell lines and MM patient cells. This effect was observed at the physiological range of VPA used to treat epileptic patients. The mechanisms underlying this increase induced a cell cycle arrest and caspase-dependent apoptosis. The potentiation of the effect of VPA by pioglitazone was mediated by higher acetylation levels of histones H3 and H4 compared to levels induced by HDAC inhibitors alone. This association reveals a new promising chemotherapeutic combination to be tested in MM.
AB - The main challenge in using chemotherapy to treat multiple myeloma (MM) is drug resistance. In order to evaluate the anti-neoplastic properties of a new drug combination in MM, two clinically available drugs, valproic acid (VPA) a histone deacetylase (HDAC) inhibitor and pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, were tested in vitro on MM cell lines and MM patient cells. The sensitivity towards VPA alone was observed on several MM cell lines tested and also on primary myeloma cells and peripheral blood mononuclear cells from healthy donors. Importantly, the addition of a PPARγ agonist to the VPA treatment increased the cytotoxic effect of VPA in a synergistic/additive manner on the different MM cell lines and MM patient cells. This effect was observed at the physiological range of VPA used to treat epileptic patients. The mechanisms underlying this increase induced a cell cycle arrest and caspase-dependent apoptosis. The potentiation of the effect of VPA by pioglitazone was mediated by higher acetylation levels of histones H3 and H4 compared to levels induced by HDAC inhibitors alone. This association reveals a new promising chemotherapeutic combination to be tested in MM.
KW - Histone deacetylase inhibitors
KW - Multiple myeloma
KW - Pioglitazone
KW - Potentiation
UR - http://www.scopus.com/inward/record.url?scp=70449370200&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/19793255/
U2 - 10.1111/j.1365-2141.2009.07902.x
DO - 10.1111/j.1365-2141.2009.07902.x
M3 - Article
C2 - 19793255
AN - SCOPUS:70449370200
SN - 0007-1048
VL - 147
SP - 662
EP - 671
JO - British Journal of Haematology
JF - British Journal of Haematology
IS - 5
ER -