Although trastuzumab provides significant clinical benefit for HER2-positive breast cancers, responses are limited by the emergence of resistance. Trastuzumab resistance is a multi-factorial phenomenon thought to arise from the presence of cancer stem cells and interactions between truncated p95HER2 and HER family members. Flubendazole (FLU) is a potent anthelmintic agent with an exceptional safety profile. Evidence also suggests that it can act as an anticancer agent in several cancer cell types. We sought to investigate the effect of FLU on apoptosis, HER2/Akt signaling, breast cancer stem cell (BCSC)-like properties and trastuzumab resistance in HER2-positive breast cancer cells. FLU treatment induced apoptosis, associated with a significant downregulation of truncated p95HER2, phospho-HER2, phospho-HER3 and phospho-Akt levels, as well as suppression of HER2/HER3 hetero-dimerization in both trastuzumab-sensitive and –resistant lines. FLU effectively targeted BCSC-like properties including aldehyde dehydrogenase 1 (ALDH1) expression and the CD44high/CD24low phenotype, concomitant with a suppression of mammosphere-forming ability. FLU administration also caused significant tumor suppression in trastuzumab-resistant xenografts, coinciding with the downregulation of BCSC-related markers and intracellular HER2. These findings highlight the mechanisms of action of FLU in overcoming trastuzumab resistance in breast cancer.
Bibliographical noteFunding Information:
This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) , funded by the Ministry of Health & Welfare , Republic of Korea (grant number: HI12C1852 ), the National Research Foundation of Korea (NRF) grant, funded by the Ministry of Science, ICT & Future Planning (MSIP, grant number: 2015R1C1A2A01053747 ) and the Ministry of Education (grant number: 2017R1A6A3A11029467 ), and was supported by a Korea University Guro Hospital Grant (grant number: O1700571 ), a Korea University Grant (research fellowship), and the Brain Korea (BK) 21 Plus Program.
© 2017 Elsevier B.V.
- Cancer stem cells
- Trastuzumab resistance
ASJC Scopus subject areas
- Cancer Research