Peroxisome proliferator-activated receptor γ agonists potentiate the cytotoxic effect of valproic acid in multiple myeloma cells

Nassera Aouali, Valérie Palissot, Victoria El-Khoury, Etienne Moussay, Bassam Janji, Sandrine Pierson, Nicolaas H.C. Brons, Laurent Kellner, Manon Bosseler, Kris Van Moer, Guy Berchem*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

15 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)662-671
Number of pages10
JournalBritish Journal of Haematology
Volume147
Issue number5
DOIs
Publication statusPublished - Dec 2009

Keywords

  • Histone deacetylase inhibitors
  • Multiple myeloma
  • Pioglitazone
  • Potentiation

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