The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells
1 Department of Pediatric Hematology and Oncology, University Childrens’ Hospital Muenster, Muenster, Germany
2 Institute of Molecular Tumor Biology, WestfalianWilhelms University, Muenster, Germany
3 Institute of Neuropathology, University Hospital Muenster, Muenster, Germany
4 Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
5 Institute of Biostatistics and Clinical Research, WestfalianWilhelms University, Muenster, Germany
6 Institute of Pharmaceutical Sciences, Freiburg, Germany
7 Childrens’ Hospital Augsburg, Swabian Childrens’ Cancer Center, Klinikum Augsburg Stenglinstr 2, Augsburg 86156, Germany
BMC Cancer 2013, 13:286 doi:10.1186/1471-2407-13-286Published: 13 June 2013
Rhabdoid tumors are highly aggressive malignancies affecting infants and very young children. In many instances these tumors are resistant to conventional type chemotherapy necessitating alternative approaches.
Proliferation assays (MTT), apoptosis (propidium iodide/annexin V) and cell cycle analysis (DAPI), RNA expression microarrays and western blots were used to identify synergism of the HDAC (histone deacetylase) inhibitor SAHA with fenretinide, tamoxifen and doxorubicin in rhabdoidtumor cell lines.
HDAC1 and HDAC2 are overexpressed in primary rhabdoid tumors and rhabdoid tumor cell lines. Targeting HDACs in rhabdoid tumors induces cell cycle arrest and apoptosis. On the other hand HDAC inhibition induces deregulated gene programs (MYCC-, RB program and the stem cell program) in rhabdoid tumors. These programs are in general associated with cell cycle progression. Targeting these activated pro-proliferative genes by combined approaches of HDAC-inhibitors plus fenretinide, which inhibits cyclinD1, exhibit strong synergistic effects on induction of apoptosis. Furthermore, HDAC inhibition sensitizes rhabdoid tumor cell lines to cell death induced by chemotherapy.
Our data demonstrate that HDAC inhibitor treatment in combination with fenretinide or conventional chemotherapy is a promising tool for the treatment of chemoresistant rhabdoid tumors.