The histone deacetylase inhibitor SAHA acts in synergism with fenretinide and doxorubicin to control growth of rhabdoid tumor cells.

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Kornelius Kerl, David Ries, Rebecca Unland, Christiane Borchert, Natalia Moreno, Martin Hasselblatt, Heribert Jürgens, Marcel Kool, Dennis Görlich, Maria Eveslage, Manfred Jung, Michael Meisterernst, Michael Frühwald
• Journal: BMC cancer (BMC Cancer) Vol. 13 Pg. 286 (Jun 13 2013) ISSN: 1471-2407 [Electronic] England
• PMID: 23764045 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Fenretinide
• Vorinostat
• Doxorubicin
• Histone Deacetylases

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Doxorubicin (administration & dosage)
• Drug Synergism
• Fenretinide (administration & dosage)
• Histone Deacetylase Inhibitors (administration & dosage)
• Histone Deacetylases (metabolism)
• Humans
• Hydroxamic Acids (administration & dosage)
• Oligonucleotide Array Sequence Analysis
• Real-Time Polymerase Chain Reaction
• Rhabdoid Tumor (metabolism, pathology)
• Vorinostat