Napabucasin Attenuates Resistance of Breast Cancer Cells to Tamoxifen by Reducing Stem Cell-Like Properties
Xueni Liu, Jianhui Huang, Yanru Xie, Yuefen Zhou, Renyi Wang, Jian Lou
Department of Medical Oncology, Lishui Municipal Central Hospital, Lishui, Zhejiang, China (mainland)
Med Sci Monit 2019; 25:8905-8912
Tamoxifen (TAM) is the first-line drug for estrogen receptor-positive (ER+) breast cancer (BC) treatment. However, its resistance is a main obstacle in clinical practice. Thus, new therapeutic agents are urgently needed to fight TAM resistance.
MATERIAL AND METHODS: Here, we constructed TAM-resistant ER+BC cells with TAM resistance, named MCF-7-R. Western blot, quantitative real-time PCR (qRT-PCR), ALDH1 activity analysis, and spheroid-forming detection were used to detect the stemness of cells and the effects of napabucasin (NP) on BC cell stemness. Cell counting kit-8 (CCK8) assay was used to evaluate the effects of NP on cell viability.
RESULTS: MCF-7-R cells exhibited higher stemness compared with the parental MCF-7 cells, which was evident by the increased spheroid formation ability at diluted concentration, aldehyde dehydrogenase (ALDH) activity, and expression of stemness critical biomarkers (Oct4, Nanog, and Sox2). Additionally, it was found that napabucasin (NP) specifically killed MCF-7-T cells, characterized by remarkably decreased IC₅₀ value. Notably, NP reduced MCF-7-R cell stemness, which was evident as the decreased stemness marker expression, spheroid-forming capacity, and ALDH1 activity. Importantly, NP attenuated TAM resistance of MCF-7-R cells and enhanced sensitivity of MCF-7 cells to TAM. Mechanistic study showed that NP inhibited STAT3 activation, and overexpression of STAT3 rescued NP-mediated inhibition of the stemness-like characteristics of MCF-7-R cells.
CONCLUSIONS: NP might be used as an adjuvant therapy for ER+ BC patients with TAM resistance.
Keywords: Colony-Forming Units Assay, Crk-Associated Substrate Protein, tamoxifen