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

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.

Escin enhanced the efficacy of sorafenib by autophagy‐mediated apoptosis in lung cancer cells

“…Besides, it also has cancer cell‐killing ability through activating intrinsic pathways and autophagy via regulating p62 and p38 (Gallelli, 2019; Zhu, Yu, et al, 2017). It also overcomes trastuzumab resistance in HER2‐positive breast cancer by targeting cancer stem‐like features (Park et al, 2022). However, its synergistic potential has never been studied.…”

“…In pre‐clinical studies, it effectively restrained tumour growth and metastasis. It was also clinically promoted in thyroid cancer patients, improving thyroid function by reducing several indices (Liu et al, 2017; Park et al, 2022; Zhu et al, 2018; Zhu, Yu, et al, 2017). However, its synergistic potential for sensitising standard anti‐cancer drugs is still unknown.…”

Acute thrombocytopenia induced by trastuzumab due to complement reaction: A case report

“…Trastuzumab is mainly used clinically for metastatic breast cancer with overexpression of HER2 ( 18 ). Trastuzumab has been shown to inhibit the proliferation of HER2-overexpressing tumor cells both in vitro and in animal studies ( 19 , 20 ). Additionally, trastuzumab is a potential mediator of antibody-dependent cell-mediated cytotoxicity ( 21 , 22 ).…”

Biopolymer Chitosan Surface Engineering with Magnesium Oxide-Pluronic-F127-Escin Nanoparticles on Human Breast Carcinoma Cell Line and Microbial Strains

“…The physical properties of the NAPs (size, shape, surface area), as well as their functionalization with the physiologically active phytomolecules (triterpene saponins) contained in the Escin component, could be linked to these significant cytotoxic effects. Escin, the primary constituent of Aesculus hippocastanum seeds, has been documented in several studies to possess powerful anti-cancer properties against breast cancer cells [35,36]. demonstrated a substantial reduction in breast cancer cell proliferation.…”