Doxorubicin overcomes resistance to drozitumab by antagonizing inhibitor of apoptosis proteins (IAPs)

Irene Zinonos, Agatha Labrinidis, Vasilios Liapis, Shelley Hay, Vasilios Panagopoulos, Mark Denichilo, Vladimir Ponomarev, Wendy Ingman, Gerald J. Atkins, David M. Findlay, Andrew C W Zannettino, Andreas Evdokiou

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background/Aim: Drozitumab is a fully human agonistic monoclonal antibody that binds to death receptor DR5 and induces apoptosis. However, drozitumab resistance is a major obstacle limiting anticancer efficacy. Materials and Methods: We examined the potential for the chemotherapeutic agent doxorubicin to overcome resistance against drozitumabresistant breast cancer cells both in vitro and in vivo. Results: Treatment with doxorubicin increased cell surface expression of DR5, reduced levels of Inhibitors of Apoptosis Proteins (cIAPs) and re-sensitised cells to drozitumab-induced apoptosis. Animals implanted with resistant breast cancer cells into the mammary fat pad and treated with a combination of drozitumab and doxorubicin showed inhibition of tumor growth and a substantial delay in tumor progression compared to untreated controls and mice treated with each agent alone. Conclusion: These results suggest that combination of drozitumab with chemotherapy and agents that modulate IAP levels could potentially be a useful strategy in the treatment of breast cancer.

Original languageEnglish
Pages (from-to)7007-7020
Number of pages14
JournalAnticancer Research
Volume34
Issue number12
Publication statusPublished - 1 Jan 2014

Keywords

  • Apo2L/TRAIL
  • Apoptosis
  • Breast cancer.
  • Chemotherapy
  • Drozitumab
  • Drug resistance

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zinonos, I., Labrinidis, A., Liapis, V., Hay, S., Panagopoulos, V., Denichilo, M., ... Evdokiou, A. (2014). Doxorubicin overcomes resistance to drozitumab by antagonizing inhibitor of apoptosis proteins (IAPs). Anticancer Research, 34(12), 7007-7020.