Pre-activation of the p53 pathway through Nutlin-3a sensitises sarcomas to drozitumab therapy

  • Authors:
    • Kathleen I. Pishas
    • Susan J. Neuhaus
    • Mark T. Clayer
    • Alaknanda Adwal
    • Michael P. Brown
    • Andreas Evdokiou
    • David F. Callen
    • Paul M. Neilsen
  • View Affiliations

  • Published online on: May 13, 2013     https://doi.org/10.3892/or.2013.2454
  • Pages: 471-477
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Abstract

The present study evaluated the efficacy of drozitumab, a human monoclonal agonistic antibody directed against death receptor 5 (DR5), as a new therapeutic avenue for the targeted treatment of bone and soft-tissue sarcomas. The antitumour activity of drozitumab as a monotherapy or in combination with Nutlin-3a was evaluated in a panel of sarcoma cell lines in vitro and human sarcoma patient samples ex vivo. Knockdown experiments were used to investigate the central role of p53 as a regulator of drozitumab cytotoxicity. Pre-activation of the p53 pathway through Nutlin-3a upregulated DR5, subsequently sensitising sarcoma cell lines and human sarcoma specimens to the pro-apoptotic effects of drozitumab. Silencing of p53 strongly decreased DR5 mRNA expression resulting in abrogation of drozitumab-induced apoptosis. Our study provides the first pre-clinical evaluation of combination therapy using p53-activating agents with drozitumab to further sensitise sarcomas to the cytotoxic effects of DR5 antibody therapy.
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July 2013
Volume 30 Issue 1

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Pishas KI, Neuhaus SJ, Clayer MT, Adwal A, Brown MP, Evdokiou A, Callen DF and Neilsen PM: Pre-activation of the p53 pathway through Nutlin-3a sensitises sarcomas to drozitumab therapy. Oncol Rep 30: 471-477, 2013.
APA
Pishas, K.I., Neuhaus, S.J., Clayer, M.T., Adwal, A., Brown, M.P., Evdokiou, A. ... Neilsen, P.M. (2013). Pre-activation of the p53 pathway through Nutlin-3a sensitises sarcomas to drozitumab therapy. Oncology Reports, 30, 471-477. https://doi.org/10.3892/or.2013.2454
MLA
Pishas, K. I., Neuhaus, S. J., Clayer, M. T., Adwal, A., Brown, M. P., Evdokiou, A., Callen, D. F., Neilsen, P. M."Pre-activation of the p53 pathway through Nutlin-3a sensitises sarcomas to drozitumab therapy". Oncology Reports 30.1 (2013): 471-477.
Chicago
Pishas, K. I., Neuhaus, S. J., Clayer, M. T., Adwal, A., Brown, M. P., Evdokiou, A., Callen, D. F., Neilsen, P. M."Pre-activation of the p53 pathway through Nutlin-3a sensitises sarcomas to drozitumab therapy". Oncology Reports 30, no. 1 (2013): 471-477. https://doi.org/10.3892/or.2013.2454