TY - JOUR
T1 - Birinapant enhances gemcitabine’s antitumor efficacy in triple-negative breast cancer by inducing intrinsic pathway–dependent apoptosis
AU - Xie, Xuemei
AU - Lee, Jangsoon
AU - Liu, Huey
AU - Pearson, Troy
AU - Lu, Alexander Y.
AU - Tripathy, Debu
AU - Devi, Gayathri R.
AU - Bartholomeusz, Chandra
AU - Ueno, Naoto T.
N1 - Funding Information:
The authors acknowledge Seayoung Lee at Duke University for discussion, Sarah Bronson of the Research Medical Library at MD Anderson Cancer Center for editorial assistance, and Wendy Schober and Nalini Patel of the Flow Cytometry and Cellular Imaging Facility at MD Anderson Cancer Center for assistance with cell-cycle distribution and apoptosis analyses. This work was supported by The University of Texas MD Anderson Cancer Center Morgan Welch Inflammatory Breast Cancer Research Program and the State of Texas Rare and Aggressive Breast Cancer Research Program (to N.T. Ueno); by MD Anderson’s Cancer Center Support Grant (P30CA016672; used the institutionally funded Flow Cytometry and Cellular Imaging Facility); by Cancer Center Support Grant (2P30CA016672-43 to The University of Texas MD Anderson Cancer Center); and by U.S. Department of Defense Grant (W81XWH-13-1-0047I, to G.R. Devi).
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-19-1160
DO - 10.1158/1535-7163.MCT-19-1160
M3 - Article
C2 - 33323457
AN - SCOPUS:85100459574
SN - 1535-7163
VL - 20
SP - 296
EP - 306
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 2
ER -