Breast Cancer Research and Treatment

, Volume 151, Issue 2, pp 281–294

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 Chen
Preclinical Study

DOI: 10.1007/s10549-015-3376-5

Cite this article as:
Kai, M., Kanaya, N., Wu, S.V. et al. Breast Cancer Res Treat (2015) 151: 281. doi:10.1007/s10549-015-3376-5

Abstract

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.

Keywords

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

Abbreviations

TNBC

Triple-negative breast cancer

BCSC

Breast cancer stem cell

ER

Estrogen receptor

PR

Progesterone receptor

HER2

Human epidermal growth factor receptor 2

HDAC

Histone deacetylase

ALDH1

Aldehyde dehydrogenase 1

EMT

Epithelial–mesenchymal transition

DMSO

Dimethyl sulfoxide

MTT

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

NSG

Non-obese diabetic/severe combined immunodeficiency gamma

Supplementary material

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
  1. 1.Department of Cancer BiologyBeckman Research Institute of the City of HopeDuarteUSA
  2. 2.Department of Medical Oncology and Therapeutics ResearchCity of HopeDuarteUSA