Small molecules targeting histone demethylase genes (KDMs) inhibit growth of temozolomide-resistant glioblastoma cells

Barbara Banelli, Antonio Daga, Alessandra Forlani, Giorgio Allemanni, Daniela Marubbi, Maria Pia Pistillo, Aldo Profumo, Massimo Romani

Research output: Contribution to journalArticle

Abstract

In glioblastoma several histone demethylase genes (KDM) are overexpressed compared to normal brain tissue and the development of Temozolomide (TMZ) resistance is accompanied by the transient further increased expression of KDM5A and other KDMs following a mechanism that we defined as "epigenetic resilience". We hypothesized that targeting KDMs may kill the cells that survive the cytotoxic therapy. We determined the effect of JIB 04 and CPI-455, two KDM inhibitors, on glioblastoma cells and found that both molecules are more effective against TMZ-resistant rather than native cells. Because of its lower IC50, we focused on JIB 04 that targets KDM5A and other KDMs as well. We have shown that this molecule activates autophagic and apoptotic pathways, interferes with cell cycle progression, inhibits cell clonogenicity and dephosphorylates Akt thus inactivating a potent pro-survival pathway. We performed combination temozolomide/JIB 04 in vitro treatments showing that these two molecules, under certain conditions, have a strong synergic effect and we hypothesize that JIB 04 intercepts the cells that escape the G2 block exerted by TMZ. Finally we studied the permeability of JIB 04 across the blood-brain barrier and found that this molecule reaches bioactive concentration in the brain; furthermore a pilot in vivo experiment in an orthotopic GB xenograft model showed a trend toward longer survival in treated mice with an Hazard Ratio of 0.5. In conclusion we propose that the combination between cytotoxic drugs and molecules acting on the epigenetic landscape may offer the opportunity to develop new therapies for this invariably lethal disease.

Original languageEnglish
Pages (from-to)34896-34910
Number of pages15
JournalOncotarget
Volume8
Issue number21
DOIs
Publication statusPublished - 2017

Keywords

  • Drug resistance
  • Epigenetics
  • Glioblastoma
  • Histone demethylase
  • Temozolomide

ASJC Scopus subject areas

  • Oncology

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