2. Academic Validation
  3. Suppression of TNBC metastasis by doxazosin, a novel dual inhibitor of c-MET/EGFR

Suppression of TNBC metastasis by doxazosin, a novel dual inhibitor of c-MET/EGFR

  • J Exp Clin Cancer Res. 2023 Nov 4;42(1):292. doi: 10.1186/s13046-023-02866-z.
Seongjae Kim 1 2,  Jung Min Park 1 2,  Soeun Park 1 2,  Eunsun Jung 1 2,  Dongmi Ko 1 2,  Minsu Park 1 2,  Juyeon Seo 1 2,  Kee Dal Nam 1 3,  Yong Koo Kang 1 3,  Kyoungmin Lee 1 3,  Lee Farrand 4,  Yoon-Jae Kim 5 6 7,  Ji Young Kim 8 9,  Jae Hong Seo 10 11 12
Affiliations

Affiliations

  • 1 Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
  • 2 Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
  • 3 Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea.
  • 4 Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, 5000, Australia.
  • 5 Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea. natureyj@nate.com.
  • 6 Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea. natureyj@nate.com.
  • 7 Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea. natureyj@nate.com.
  • 8 Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea. amaryllis1210@gmail.com.
  • 9 Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea. amaryllis1210@gmail.com.
  • 10 Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea. cancer@korea.ac.kr.
  • 11 Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul, 02841, Republic of Korea. cancer@korea.ac.kr.
  • 12 Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, 148 Gurodong-ro, Guro-gu, Seoul, 08308, Republic of Korea. cancer@korea.ac.kr.
PMID: 37924112 DOI: 10.1186/s13046-023-02866-z
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.

Keywords

Cancer stem cells; Doxazosin; Drug accessibility; EGFR; Metastasis; Triple-negative breast cancer; c-MET.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P9977
    99.90%, EGFR-MET Dual Antibody