Peroxisome proliferator-activated receptor gamma agonists potentiate the cytotoxic effect of valproic acid in multiple myeloma cells.
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 (PPARgamma) 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 PPARgamma 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.
Aouali
Nassera
N
Laboratoire d'Hémato-Cancérologie Expérimentale, CRP-Santé, Val Fleuri, Luxembourg.
Palissot
Valérie
V
El-Khoury
Victoria
V
Moussay
Etienne
E
Janji
Bassam
B
Pierson
Sandrine
S
Brons
Nicolaas H C
NH
Kellner
Laurent
L
Bosseler
Manon
M
Van Moer
Kris
K
Berchem
Guy
G
D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004357:Drug Synergism; D006657:Histones / Q000378:metabolism; D006801:Humans; D009101:Multiple Myeloma / Q000473:pathology*; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014635:Valproic Acid / Q000494:pharmacology*
D000970:Antineoplastic Agents; D006657:Histones; D047495:PPAR gamma; D045162:Thiazolidinediones; D014635:Valproic Acid; D020169:Caspases; D000077205:Pioglitazone