Author:
Park Soeun,Park Jung Min,Park Minsu,Ko Dongmi,Kim Seongjae,Seo Juyeon,Nam Kee Dal,Jung Eunsun,Farrand Lee,Kim Yoon-Jae,Kim Ji Young,Seo Jae Hong
Abstract
Abstract
Background
The emergence of de novo or intrinsic trastuzumab resistance is exceedingly high in breast cancer that is HER2 positive and correlates with an abundant cancer stem cell (CSC)-like population. We sought to examine the capacity of β-escin, an anti-inflammatory drug, to address trastuzumab resistance in HER2-positive breast cancer cells.
Methods
The effect of β-escin on trastuzumab-resistant and -sensitive cell lines in vitro was evaluated for apoptosis, expression of HER2 family members, and impact on CSC-like properties. An in vivo model of trastuzumab-resistant JIMT-1 was used to examine the efficacy and toxicity of β-escin.
Results
β-escin induced mitochondrial-mediated apoptosis accompanied by reactive oxygen species (ROS) production and increased active p18Bax fragmentation, leading to caspase-3/-7 activation. Attenuation of CSC-related features by β-escin challenge was accompanied by marked reductions in CD44high/CD24low stem-like cells and aldehyde dehydrogenase 1 (ALDH1) activity as well as hindrance of mammosphere formation. β-escin administration also significantly retarded tumor growth and angiogenesis in a trastuzumab-resistant JIMT-1 xenograft model via downregulation of CSC-associated markers and intracellular domain HER2. Importantly, β-escin selectively inhibited malignant cells and was less toxic to normal mammary cells, and no toxic effects were found in liver and kidney function in animals.
Conclusions
Taken together, our findings highlight β-escin as a promising candidate for the treatment of trastuzumab-resistant HER2-positive breast cancers.
Funder
National Research Foundation of Korea
Korea Health Industry Development Institute
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Genetics,Oncology
Cited by
6 articles.
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