Rapamycin increases neuroblastoma xenograft and host stromal derived osteoprotegerin inhibiting osteolytic bone disease in a bone metastasis model
| Autor: | Lisa M. McGregor, Joseph E. Hartwich, Catherine Y.C. Ng, Wayne L. Furman, Jillian M. McLaughlin, Andrew M. Davidoff, W. Shannon Orr, Yunyu Spence |
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| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
musculoskeletal diseases
medicine.medical_specialty Stromal cell Bone disease Bone Neoplasms Enzyme-Linked Immunosorbent Assay Mice SCID Article Drug Administration Schedule Mice Neuroblastoma Osteoprotegerin Internal medicine Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans Receptor PI3K/AKT/mTOR pathway Sirolimus Antibiotics Antineoplastic Dose-Response Relationship Drug business.industry Reverse Transcriptase Polymerase Chain Reaction Bone metastasis General Medicine medicine.disease Endocrinology Fractures Spontaneous Treatment Outcome Pediatrics Perinatology and Child Health Cancer research Surgery business Biomarkers Injections Intraperitoneal medicine.drug |
| Popis: | Osteoprotegerin (OPG) is a decoy receptor for the Receptor of NF-κB (RANK) ligand that can inhibit osteoclastogenesis. Previous studies have suggested that Mammalian Target of Rapamycin (mTOR) inhibition upregulates OPG production. We tested the hypothesis that the mTOR inhibitor rapamycin could inhibit neuroblastoma bone metastases through its action on OPG.An orthotopic model of bone metastasis was established. Mice with established disease were subsequently treated with rapamycin (5mg/kg IP daily) or vehicle control (DMSO 1:1000). X-rays were obtained twice a week to detect pathologic fractures. Serum OPG levels were measured by ELISA after two weeks of treatment.Mice with bone disease receiving rapamycin had increased serum levels of OPG in the CHLA-20 mice compared to controls (36.89 pg/mL ± 3.90 vs 18.4 pg/mL ± 1.67, p=0.004) and NB1691 tumor-bearing groups (46.03 ± 2.67 pg/mL vs 17.96 ± 1.84pg/mL, p=0.001), and a significantly longer median time to pathologic fractures with CHLA-20 (103 days vs 74.5 days, p=0.014) and NB1691 xenografts.In a xenograft model, increased OPG expression correlated with a delay to pathologic fracture suggesting a potential role for mTOR inhibitors in the treatment of neuroblastoma bone metastases. |
| Databáze: | OpenAIRE |
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