Breast Cancer Research and Treatment

, Volume 151, Issue 2, pp 281–294 | Cite as

Targeting breast cancer stem cells in triple-negative breast cancer using a combination of LBH589 and salinomycin

  • Masaya Kai
  • Noriko Kanaya
  • Shang V. Wu
  • Carlos Mendez
  • Duc Nguyen
  • Thehang Luu
  • Shiuan ChenEmail author
Preclinical Study


The aim of this study is to investigate the efficacy of combining a histone deacetylase inhibitor (LBH589) and a breast cancer stem cells (BCSC)-targeting agent (salinomycin) as a novel combination therapy for triple-negative breast cancer (TNBC). We performed in vitro studies using the TNBC cell lines to examine the combined effect. We used the mammosphere and ALDEFLUOR assays to estimate BCSC self-renewal capacity and distribution of BCSCs, respectively. Synergistic analysis was performed using CalcuSyn software. For in vivo studies, aldehyde dehydrogenase 1 ALDH1-positive cells were injected into non-obese diabetic/severe combined immunodeficiency gamma (NSG) mice. After tumor formation, mice were treated with LBH589, salinomycin, or in combination. In a second mouse model, HCC1937 cells were first treated with each treatment and then injected into NSG mice. For mechanistic analysis, immunohistochemistry and Western blot analysis were performed using cell and tumor samples. HCC1937 cells displayed BCSC properties including self-renewal capacity, an ALDH1-positive cell population, and the ability to form tumors. Treatment of HCC1937 cells with LBH589 and salinomycin had a potent synergistic effect inhibiting TNBC cell proliferation, ALDH1-positive cells, and mammosphere growth. In xenograft mouse models treated with LBH589 and salinomycin, the drug combination effectively and synergistically inhibited tumor growth of ALDH1-positive cells. The drug combination exerted its effects by inducing apoptosis, arresting the cell cycle, and regulating epithelial–mesenchymal transition (EMT). Combination of LBH589 and salinomycin has a synergistic inhibitory effect on TNBC BCSCs by inducing apoptosis, arresting the cell cycle, and regulating EMT; with no apparent associated severe toxicity. This drug combination could therefore offer a new targeted therapeutic strategy for TNBC and warrants further clinical study in patients with TNBC.


Triple-negative breast cancer (TNBC) Breast cancer stem cells (BCSCs) Histone deacetylase (HDAC) inhibitor LBH589 (panobinostat) Salinomycin 



Triple-negative breast cancer


Breast cancer stem cell


Estrogen receptor


Progesterone receptor


Human epidermal growth factor receptor 2


Histone deacetylase


Aldehyde dehydrogenase 1


Epithelial–mesenchymal transition


Dimethyl sulfoxide


3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide


Non-obese diabetic/severe combined immunodeficiency gamma



We thank Sofia Loera for assistance with IHC staining, Lucy Brown for assistance with the flow cytometry analyses, Donna Isbell and Lauren Ratcliffe for animal care, and Nicola Solomon, Ph.D., for assistance in writing and editing the manuscript. The research was supported by Susan G. Komen for the Cure (KG080161), the National Cancer Institute (P30 CA033572), the City of Hope Women’s Cancers Program Idol Research Project Award (NK and TL), and the Carr-Baird family.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10549_2015_3376_MOESM1_ESM.docx (93 kb)
(DOC 94 kb)


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Masaya Kai
    • 1
  • Noriko Kanaya
    • 1
  • Shang V. Wu
    • 1
  • Carlos Mendez
    • 1
  • Duc Nguyen
    • 1
  • Thehang Luu
    • 2
  • Shiuan Chen
    • 1
    Email author
  1. 1.Department of Cancer BiologyBeckman Research Institute of the City of HopeDuarteUSA
  2. 2.Department of Medical Oncology and Therapeutics ResearchCity of HopeDuarteUSA

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