한빛사논문
- 조회596
Seongjae Kim1,2, Jung Min Park1,2, Soeun Park1,2, Eunsun Jung1,2, Dongmi Ko1,2, Minsu Park1,2, Juyeon Seo1,2, Kee Dal Nam1,3, Yong Koo Kang1,3, Kyoungmin Lee1,3, Lee Farrand4, Yoon‑Jae Kim1,2,3*, Ji Young Kim1,3* and Jae Hong Seo1,2,3*
1Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea.
2Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 02841, Republic of Korea.
3Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 148 Gurodong‑ro, Guro‑gu, Seoul 08308, Republic of Korea.
4Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia 5000, Australia.
Corresponding authors : Correspondence to Yoon-Jae Kim, Ji Young Kim or Jae Hong Seo.
Abstract
Background
Triple-negative breast cancer (TNBC) is characterized by aggressive growth and a high propensity for recurrence and metastasis. Simultaneous overexpression of c-MET and EGFR in TNBC is associated with worse clinicopathological features and unfavorable outcomes. Although the development of new c-MET inhibitors and the emergence of 3rd-generation EGFR inhibitors represent promising treatment options, the high costs involved limit the accessibility of these drugs. In the present study, we sought to investigate the therapeutic potential of doxazosin (DOXA), a generic drug for benign prostate hyperplasia, in targeting TNBC.
Methods
The effect of DOXA on TNBC cell lines in vitro was evaluated in terms of cell viability, apoptosis, c-MET/EGFR signaling pathway, molecular docking studies and impact on cancer stem cell (CSC)-like properties. An in vivo metastatic model with CSCs was used to evaluate the efficacy of DOXA.
Results
DOXA exhibits notable anti-proliferative effects on TNBC cells by inducing apoptosis via caspase activation. Molecular docking studies revealed the direct interaction of DOXA with the tyrosine kinase domains of c-MET and EGFR. Consequently, DOXA disrupts important survival pathways including AKT, MEK/ERK, and JAK/STAT3, while suppressing CSC-like characteristics including CD44high/CD24low subpopulations, aldehyde dehydrogenase 1 (ALDH1) activity and formation of mammospheres. DOXA administration was found to suppress tumor growth, intra- and peri-tumoral angiogenesis and distant metastasis in an orthotopic allograft model with CSC-enriched populations. Furthermore, no toxic effects of DOXA were observed in hepatic or renal function.
Conclusions
Our findings highlight the potential of DOXA as a therapeutic option for metastatic TNBC, warranting further investigation.
논문정보
- Research article
- 2023년 11월 (BRIC 등록일 2023-11-06)
- 국내 연구진
- 의약학 > 종양의학
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