ß-Escin overcomes trastuzumab resistance in HER2-positive breast cancer by targeting cancer stem-like features.
Cancer Cell Int
; 22(1): 289, 2022 Sep 20.
Article
em En
| MEDLINE
| ID: mdl-36127671
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 ß-escin, an anti-inflammatory drug, to address trastuzumab resistance in HER2-positive breast cancer cells.METHODS:
The effect of ß-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 ß-escin.RESULTS:
ß-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 ß-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. ß-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, ß-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 ß-escin as a promising candidate for the treatment of trastuzumab-resistant HER2-positive breast cancers.
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Base de dados:
MEDLINE
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article