Response of preclinical medulloblastoma models to combination therapy with 13-cis retinoic acid and suberoylanilide hydroxamic acid (SAHA).
OBJECTIVE
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.


METHODS
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.
Spiller
Susan E
SE
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. sspiller@peds.uab.edu
Ditzler
Sally H
SH
Pullar
Barbara J
BJ
Olson
James M
JM
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000187:drug effects; D045744:Cell Line, Tumor; D002528:Cerebellar Neoplasms / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D015474:Isotretinoin / Q000008:administration & dosage*; D008527:Medulloblastoma / Q000188:drug therapy*; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000187:drug effects; D000077337:Vorinostat
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D006877:Hydroxamic Acids; D016212:Transforming Growth Factor beta; D000077337:Vorinostat; D015474:Isotretinoin; D002945:Cisplatin