β-Escin overcomes trastuzumab resistance in HER2-positive breast cancer by targeting cancer stem-like features

Soeun Park, Jung Min Park, Minsu Park, Dongmi Ko, Seongjae Kim, Juyeon Seo, Kee Dal Nam, Eunsun Jung, Lee Farrand, Yoon Jae Kim, Ji Young Kim, Jae Hong Seo

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Article number289
JournalCancer Cell International
Volume22
Issue number1
DOIs
Publication statusPublished - 2022 Dec

Keywords

  • Cancer stem cells
  • Drug repurposing
  • HER2-positive breast cancer
  • Trastuzumab resistance
  • p95HER2
  • β-escin

ASJC Scopus subject areas

  • Oncology
  • Genetics
  • Cancer Research

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