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Molecular Cancer Therapeutics
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Small Molecule Therapeutics

Birinapant Enhances Gemcitabine's Antitumor Efficacy in Triple-Negative Breast Cancer by Inducing Intrinsic Pathway–Dependent Apoptosis

Xuemei Xie, Jangsoon Lee, Huey Liu, Troy Pearson, Alexander Y. Lu, Debu Tripathy, Gayathri R. Devi, Chandra Bartholomeusz and Naoto T. Ueno
Xuemei Xie
1Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • ORCID record for Xuemei Xie
  • For correspondence: nueno@mdanderson.org xxie2@mdanderson.org
Jangsoon Lee
1Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Huey Liu
1Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Troy Pearson
1Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Alexander Y. Lu
2Department of Bioengineering, Rice University, Houston, Texas.
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Debu Tripathy
1Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Gayathri R. Devi
3Department of Surgery, Division of Surgical Sciences, Duke Cancer Institute, Duke University School of Medicine, North Carolin.
4Women's Cancer Program, Duke Cancer Institute, Duke University School of Medicine, North Carolina.
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Chandra Bartholomeusz
1Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Naoto T. Ueno
1Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • For correspondence: nueno@mdanderson.org xxie2@mdanderson.org
DOI: 10.1158/1535-7163.MCT-19-1160 Published February 2021
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Abstract

Triple-negative breast cancer (TNBC) is the most aggressive subgroup of breast cancer, and patients with TNBC have few therapeutic options. Apoptosis resistance is a hallmark of human cancer, and apoptosis regulators have been targeted for drug development for cancer treatment. One class of apoptosis regulators is the inhibitors of apoptosis proteins (IAPs). Dysregulated IAP expression has been reported in many cancers, including breast cancer, and has been shown to be responsible for resistance to chemotherapy. Therefore, IAPs have become attractive molecular targets for cancer treatment. Here, we first investigated the antitumor efficacy of birinapant (TL32711), a biindole-based bivalent mimetic of second mitochondria-derived activator of caspases (SMACs), in TNBC. We found that birinapant as a single agent has differential antiproliferation effects in TNBC cells. We next assessed whether birinapant has a synergistic effect with commonly used anticancer drugs, including entinostat (class I histone deacetylase inhibitor), cisplatin, paclitaxel, voxtalisib (PI3K inhibitor), dasatinib (Src inhibitor), erlotinib (EGFR inhibitor), and gemcitabine, in TNBC. Among these tested drugs, gemcitabine showed a strong synergistic effect with birinapant. Birinapant significantly enhanced the antitumor activity of gemcitabine in TNBC both in vitro and in xenograft mouse models through activation of the intrinsic apoptosis pathway via degradation of cIAP2 and XIAP, leading to apoptotic cell death. Our findings demonstrate the therapeutic potential of birinapant to enhance the antitumor efficacy of gemcitabine in TNBC by targeting the IAP family of proteins.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2021;20:296–306

  • Received December 24, 2019.
  • Revision received September 1, 2020.
  • Accepted November 30, 2020.
  • Published first December 15, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 20 (2)
February 2021
Volume 20, Issue 2
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Birinapant Enhances Gemcitabine's Antitumor Efficacy in Triple-Negative Breast Cancer by Inducing Intrinsic Pathway–Dependent Apoptosis
Xuemei Xie, Jangsoon Lee, Huey Liu, Troy Pearson, Alexander Y. Lu, Debu Tripathy, Gayathri R. Devi, Chandra Bartholomeusz and Naoto T. Ueno
Mol Cancer Ther February 1 2021 (20) (2) 296-306; DOI: 10.1158/1535-7163.MCT-19-1160

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Birinapant Enhances Gemcitabine's Antitumor Efficacy in Triple-Negative Breast Cancer by Inducing Intrinsic Pathway–Dependent Apoptosis
Xuemei Xie, Jangsoon Lee, Huey Liu, Troy Pearson, Alexander Y. Lu, Debu Tripathy, Gayathri R. Devi, Chandra Bartholomeusz and Naoto T. Ueno
Mol Cancer Ther February 1 2021 (20) (2) 296-306; DOI: 10.1158/1535-7163.MCT-19-1160
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Molecular Cancer Therapeutics
eISSN: 1538-8514
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