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

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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.

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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

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Acknowledgments

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.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Cancer Biology, Beckman Research Institute of the City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA

    Masaya Kai, Noriko Kanaya, Shang V. Wu, Carlos Mendez, Duc Nguyen & Shiuan Chen

  2. Department of Medical Oncology and Therapeutics Research, City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA

    Thehang Luu

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  1. Masaya Kai
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Correspondence to Shiuan Chen.

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Kai, M., Kanaya, N., Wu, S.V. et al. Targeting breast cancer stem cells in triple-negative breast cancer using a combination of LBH589 and salinomycin. Breast Cancer Res Treat 151, 281–294 (2015). https://doi.org/10.1007/s10549-015-3376-5

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