Abstract
BackgroundRhabdoid 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.MethodsProliferation 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.ResultsHDAC1 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.ConclusionOur data demonstrate that HDAC inhibitor treatment in combination with fenretinide or conventional chemotherapy is a promising tool for the treatment of chemoresistant rhabdoid tumors.
Highlights
Rhabdoid tumors are highly aggressive malignancies affecting infants and very young children
Some pathways drivingoncogenesis are defined in rhabdoid tumors: In SMARCB1 negative tumors oncogenes [17,18,19,20] and tumor cascades such as the sonic hedgehog pathway are activated [19]
Histone deacetylase (HDAC) are highly expressed in primary rhabdoid tumors and rhabdoid tumor cell lines Aberrant expression of different HDACs has been observed in various tumors [1,2,9] and has been linked to tumor growth progression and poor outcome [27]
Summary
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. Altered states of chromatin in cancer cells are a promising novel target for therapeutic strategies in the treatment of malignant tumors. HDAC inhibitors counteract cell proliferation and induce apoptosis by altering histone tails and non-histone targets including transcription factors, hormone receptors, signal transducers and molecular chaperones [3]. The majority of rhabdoid tumors exhibit biallelic alterations in the tumor suppressor gene SMARCB1. SMARCB1 and EZH2 exhibit antagonistic functions in the regulation of stem cellassociated programs. In rhabdoid tumors loss of SMARCB1 activates those programs [21]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
