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Erschienen in: Breast Cancer Research and Treatment 2/2015

01.06.2015 | Preclinical Study

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

verfasst von: Masaya Kai, Noriko Kanaya, Shang V. Wu, Carlos Mendez, Duc Nguyen, Thehang Luu, Shiuan Chen

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 2/2015

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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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Metadaten
Titel
Targeting breast cancer stem cells in triple-negative breast cancer using a combination of LBH589 and salinomycin
verfasst von
Masaya Kai
Noriko Kanaya
Shang V. Wu
Carlos Mendez
Duc Nguyen
Thehang Luu
Shiuan Chen
Publikationsdatum
01.06.2015
Verlag
Springer US
Erschienen in
Breast Cancer Research and Treatment / Ausgabe 2/2015
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-015-3376-5

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