Abstract
Purpose Current medulloblastoma therapy, surgery, radiation, and chemotherapy, is unacceptably toxic. However, 13-cis retinoic acid (RA) and SAHA, a histone deacetylase inhibitor, have each been shown to induce apoptosis in medulloblastoma cultures and mouse models. Both drugs cross the blood brain barrier, have been given safely to children, and achieve brain concentrations that are at or near therapeutic levels. Retinoic acid acts by transcriptionally activating bone morphogenetic protein-2 (BMP-2) and SAHA facilitates transcriptional activity through chromatin accessibility. We tested the hypothesis that these drugs additively induce BMP-2 transcription and apoptosis. Experimental design RA + SAHA induction of BMP-2 transcription and apoptosis in medulloblastoma cultures was evaluated. Subsequently the response of mouse medulloblastomas to these two agents in the presence and absence of cisplatin was evaluated. Results BMP-2 transcription multiplied 3-fold with addition of RA to culture, and 7-fold with both agents. The IC50 of SAHA was reduced by 40% when low dose RA was added. Interestingly, a p38 MAP kinase inhibitor that partially blocks RA-induced apoptosis did not inhibit the activity of RA + SAHA. Flank D283 tumors in athymic mice had slower growth in the RA + SAHA arm than single drug or control arms. Intracranial tumors in ND2:SmoA1 mice treated with RA + SAHA + cisplatin showed a 4-fold increase in apoptosis over controls, and a 2-fold increase over animals receiving only SAHA or RA + SAHA. Conclusions RA + SAHA additively induce BMP-2 transcription and medulloblastoma apoptosis. The combination may act through a p38 MAPK independent mechanism. Efficacy increased with cisplatin, which has implications for clinical trial design.
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Acknowledgments
The authors wish to acknowledge Dr. Victoria Richon at Merck for her helpful discussions and generous contribution of SAHA. We also thank Dr. Andrew Hallahan and Stacey Hansen for helpful discussions, and Dr. Michael LeBlanc of the Southwest Oncology Group for assistance with statistical methods. This work was supported by NIH grants R01 CA114567-01A1 (JMO), R01 CA112350-02 (JMO), and U01 CA814547-07 (J. R. Geyer, PI) as well as the Damon Runyon Foundation (JMO) the Emily Dorfman Foundation through the American Brain Tumor Association (SES) and the Jordyn Dukelow Memorial Guild of Seattle Children’s Hospital (SES).
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Spiller, S.E., Ditzler, S.H., Pullar, B.J. et al. Response of preclinical medulloblastoma models to combination therapy with 13-cis retinoic acid and suberoylanilide hydroxamic acid (SAHA). J Neurooncol 87, 133–141 (2008). https://doi.org/10.1007/s11060-007-9505-1
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DOI: https://doi.org/10.1007/s11060-007-9505-1