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Research ArticleExperimental Studies

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 and ANDREAS EVDOKIOU
Anticancer Research December 2014, 34 (12) 7007-7020;
IRENE ZINONOS
1Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia
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AGATHA LABRINIDIS
1Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia
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VASILIOS LIAPIS
1Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia
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SHELLEY HAY
1Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia
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VASILIOS PANAGOPOULOS
1Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia
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MARK DENICHILO
1Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia
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VLADIMIR PONOMAREV
2Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, U.S.A.
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WENDY INGMAN
5Discipline of Surgery, Haematology - Oncology, Breast Biology Cancer Unit, Basil Hetzel Institute, University of Adelaide, Adelaide, SA, Australia
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GERALD J. ATKINS
3Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA, Australia
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DAVID M. FINDLAY
3Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide, SA, Australia
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ANDREW C.W. ZANNETTINO
4Myeloma Research Laboratory, School of Medical Sciences, Faculty of Health Science and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia
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ANDREAS EVDOKIOU
1Discipline of Surgery, Breast Cancer Research Unit, Basil Hetzel Institute and Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia
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  • For correspondence: andreas.evdokiou@adelaide.edu.au
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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 drozitumab-resistant 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.

  • Apoptosis
  • Apo2L/TRAIL
  • drozitumab
  • drug resistance
  • chemotherapy
  • breast cancer
  • Received August 6, 2014.
  • Revision received September 10, 2014.
  • Accepted September 15, 2014.
  • Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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Anticancer Research: 34 (12)
Anticancer Research
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December 2014
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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
Anticancer Research Dec 2014, 34 (12) 7007-7020;

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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
Anticancer Research Dec 2014, 34 (12) 7007-7020;
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Keywords

  • apoptosis
  • Apo2L/TRAIL
  • drozitumab
  • drug resistance
  • chemotherapy
  • Breast cancer
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