Nutlin-3 treatment spares cisplatin-induced inhibition of bone healing while maintaining osteosarcoma toxicity

Kimo C. Stine, Elizabeth C. Wahl, Lichu Liu, Robert A. Skinner, Jaclyn VanderSchilden, Robert C. Bunn, Corey O. Montgomery, James Aronson, David L. Becton, Richard W. Nicholas, Christopher J. Swearingen, Larry J. Suva, Charles K. Lumpkin

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The majority of Osteosarcoma (OS) patients are treated with a combination of chemotherapy, resection, and limb salvage protocols. These protocols include distraction osteogenesis (DO), which is characterized by direct new bone formation. Cisplatin (CDP) is extensively used for OS chemotherapy and recent studies, using a mouse DO model, have demonstrated that CDP has profound negative effects on bone repair. Recent oncological therapeutic strategies are based on the use of standard cytotoxic drugs plus an assortment of biologic agents. Here we demonstrate that the previously reported CDP-associated inhibition of bone repair can be modulated by the administration of a small molecule p53 inducer (nutlin-3). The effects of nutlin-3 on CDP osteotoxicity were studied using both pre- and post-operative treatment models. In both cases the addition of nutlin-3, bracketing CDP exposure, demonstrated robust and significant bone sparing activity (p < 0.01–0.001). In addition the combination of nutlin-3 and CDP induced equivalent OS tumor killing in a xenograft model. Collectively, these results demonstrate that the induction of p53 peri-operatively protects bone healing from the toxic effects of CDP, while maintaining OS toxicity.

Original languageEnglish
Pages (from-to)1716-1724
Number of pages9
JournalJournal of Orthopaedic Research
Volume34
Issue number10
DOIs
StatePublished - Oct 1 2016

Bibliographical note

Funding Information:
The authors' acknowledge the expert assistance of William Hogue and Phaedra Yount. This research was supported, in part, by (1) the Children's University Medical Group Fund Grant Program, the Arkansas Children's Hospital Research Institute, (2) the Arkansas Biosciences Institute, funded by the Arkansas Tobacco Settlement Plan and administered by Arkansas Children's Hospital Research Institute, (3) UAMS Pediatric Hematology/ Oncology Division, (4) Carl L. Nelson Endowed Chair in Orthopaedic Creativity and UAMS Translational Research Institute supported by the National Institutes of Health National Center for Research Resources grant UL1 RR029884, (5) NIH National Center for Research Resources Grant #1CORR16517-01, by Arkansas Biosciences Institute and (6) National Institutes of Health R01 CA166060.

Publisher Copyright:
© 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Keywords

  • chemotherapy
  • cisplatin
  • distraction osteogenesis
  • limb salvage
  • nutlin-3

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine

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