Klin Padiatr 2012; 224 - A2
DOI: 10.1055/s-0032-1320170

Effects of histone methyltransferase inhibitor 3-Deazaneoplanocin (DZNep) on rhabdoid tumor cell lines

C Borchardt 1, R Unland 1, D Clemens 1, K Kerl 1, G Hempel 2, MC Frühwald 1, 3
  • 1Department of Pediatric Hematology and Oncology, University Childrens Hospital, University of Münster, Münster, Germany
  • 2Department of Pharmaceutical and Medical Chemistry – Clinical Pharmacy – University of Münster, Germany
  • 3Childrens Hospital Augsburg, Augsburg, Germany

Rhabdoid tumors (RT) are highly aggressive pediatric tumors which arise in brain, heart, kidney, liver and other soft tissues. Although the prognosis of RT patients has improved, it still remains poor due to an initial response to conventional chemotherapy followed by resistance.

Rhabdoid tumors are characterized by mutations in genes of the SWI/SNF chromatin remodeling complex, most often biallelic inactivation of SNF5, the core subunit of this complex. It has been shown, that SNF5 acts as a direct inhibitor of the enhancer of zeste homologe (EZH2). EZH2 is a histone methyltransferase, which catalyses the trimethylation of H3K27 and interacts with DNA methyltransferases as well as with histone deacetylases (HDAC). It is thus associated with gene silencing. Furthermore, EZH2 is known to be involved in proliferation, aggressive cell growth as well as stem cell maintenance. Accordingly EZH2 is an interesting therapeutic target in RTs.

The objective of our study was to investigate whether inhibition of EZH2 using the 3-Deazaneoplanocin (DZNep) in combination with conventional chemotherapeutics may offer a potetntial therapy for children with RT. The methyltransferase inhibitor DZNep has been demonstrated to inhibit the catalytic activity of EZH2. By performing MTT assays we first investigated the proliferation rate of various rhabdoid tumor cell lines following treatment with DZNzep alone or in combination with conventional chemotherapeutics and new anticancer drugs. Combination treatment demonstrated synergistic effects on the proliferation rate in vitro. The effect of DZNep and combinatorial treatment on apoptosis, colony forming and cell cycle progression was analyzed in vitro.

Here, we present first data of functional analyses of rhabdoid tumor cell lines treated with DZNep alone and in combination with selected anticancer drugs.