Flubendazole elicits anti-metastatic effects in triple-negative breast cancer via STAT3 inhibition

Eunhye Oh, Yoon Jae Kim, Hyunsook An, Daeil Sung, Tae Min Cho, Lee Farrand, Seojin Jang, Jae Hong Seo, Ji Young Kim

Research output: Contribution to journalArticlepeer-review

69 Citations (Scopus)


Tumor metastasis remains the cause of 90% of cancer-related deaths. Cancer stem cells (CSC) are thought to be responsible for the aggressive and metastatic nature of triple-negative breast cancers (TNBC), and new therapeutic strategies are being devised to target them. Flubendazole (FLU) is a widely used anthelmintic agent that also exhibits anticancer activity in several cancer types. The aim of this study was to characterize the mechanism of action of FLU on breast cancer stem cell (BCSC)-like properties and metastasis in TNBC. FLU treatment caused a significant induction of apoptosis, accompanied by G2/M phase accumulation, caspase-3/-7 activation and the dysregulation of STAT3 activation in TNBC cells. The latter phenomenon was associated with impairment of cancer stem-like traits, concomitant with a reduction in the CD24low/CD44high, CD24high/CD49fhigh subpopulation, ALDH1 activity and mammosphere formation. The BCSC-enriched populations exhibited enhanced metastasis with higher STAT3 activation, while FLU administration inhibited tumor growth, angiogenesis and lung and liver metastasis, coinciding with decreased MMP-2 and MMP-9 levels in circulating blood. FLU kills not only rapid proliferating tumor cells but also effectively eradicates BCSC-like cells in vitro and in vivo. Our findings warrant further investigation of FLU as a treatment for metastatic TNBC.

Original languageEnglish
Pages (from-to)1978-1993
Number of pages16
JournalInternational Journal of Cancer
Issue number8
Publication statusPublished - 2018 Oct 15

Bibliographical note

Funding Information:
Key words: flubendazole, triple-negative breast cancer, cancer stem cells, STAT3, metastasis Abbreviations: ALDH1: aldehyde dehydrogenase 1; BCSCs: breast cancer stem cells; CSC: cancer stem cells; EMT: epithelial-mesenchymal transition; FLU: flubendazole; MVD: microvessel density; STAT3: signal transducer and activator of transcription 3; TNBC: triple-negative breast cancer cells; VEGF: vascular endothelial growth factor Additional Supporting Information may be found in the online version of this article. E.O. and Y-J.K. contributed equally to this work Conflict of Interest: The authors declare no conflict of interest. Grant sponsor: Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) and National R&D Program for Cancer Control; Grant sponsor: Ministry of Health & Welfare, Republic of Korea; Grant number: HI12C1852, 1720340; Grant sponsor: National Research Foundation of Korea (NRF), Korea government (MSIT); Grant numbers: 2015R1C1A2A01053747, 2018R1A2B6005347, 2018R1D1A1B07045416; Grant sponsor: Ministry of Education; Grant number: 2017R1A6A3A11029467; Grant sponsor: Korea University Guro Hospital; Grant number: O1700571; Grant sponsor: Korea University; Grant sponsor: Brain Korea (BK) 21 Plus Program DOI: 10.1002/ijc.31585 History: Received 1 Dec 2017; Accepted 12 Apr 2018; Online 9 May 2017 Correspondence to: Jae Hong Seo, Korea University, Guro Hospital Campus, 97 Gurodong-gil, Guro-gu, Seoul 152-703, Republic of Korea, Tel.: 182-2-2626-3059, Fax: 182-2-862-6453, E-mail: cancer@korea.ac.kr; or Ji Young Kim, Korea University, Guro Hospital Campus, 97 Gurodong-gil, Guro-gu, Seoul 152-703, Republic of Korea, Tel.: 182-2-2626-1898, Fax: 182-2-862-6453, E-mail: amaryllis1210@gmail.com

Publisher Copyright:
© 2018 UICC


  • STAT3
  • cancer stem cells
  • flubendazole
  • metastasis
  • triple-negative breast cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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