Towards the first targeted therapy for triple-negative breast cancer: Repositioning of clofazimine as a chemotherapy-compatible selective Wnt pathway inhibitor.

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Version: Author's accepted manuscript
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_E7565389B437
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Towards the first targeted therapy for triple-negative breast cancer: Repositioning of clofazimine as a chemotherapy-compatible selective Wnt pathway inhibitor.
Journal
Cancer letters
Author(s)
Ahmed K., Koval A., Xu J., Bodmer A., Katanaev V.L.
ISSN
1872-7980 (Electronic)
ISSN-L
0304-3835
Publication state
Published
Issued date
01/05/2019
Peer-reviewed
Oui
Volume
449
Pages
45-55
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Wnt signaling is overactivated in triple-negative breast cancer (TNBC) and several other cancers, and its suppression emerges as an effective anticancer treatment. However, no drugs targeting the Wnt pathway exist on the market nor in advanced clinical trials. Here we provide a comprehensive body of preclinical evidence that an anti-leprotic drug clofazimine is effective against TNBC. Clofazimine specifically inhibits canonical Wnt signaling in a panel of TNBC cells in vitro. In several mouse xenograft models of TNBC, clofazimine efficiently suppresses tumor growth, correlating with in vivo inhibition of the Wnt pathway in the tumors. Clofazimine is well compatible with doxorubicin, exerting additive effects on tumor growth suppression, producing no adverse effects. Its excellent and well-characterized pharmacokinetics profile, lack of serious adverse effects at moderate (yet therapeutically effective) doses, its combinability with cytotoxic therapeutics, and the novel mechanistic mode of action make clofazimine a prime candidate for the repositioning clinical trials. Our work may bring forward the anti-Wnt targeted therapy, desperately needed for thousands of patients currently lacking targeted treatments.
Keywords
Animals, Antineoplastic Combined Chemotherapy Protocols/administration & dosage, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Cell Line, Tumor, Cell Proliferation/drug effects, Cell Survival/drug effects, Clofazimine/administration & dosage, Clofazimine/pharmacology, Doxorubicin/administration & dosage, Doxorubicin/therapeutic use, Drug Repositioning, Female, Gene Expression Regulation, Neoplastic/drug effects, Humans, Mice, Neoplasm Transplantation, Triple Negative Breast Neoplasms/drug therapy, Triple Negative Breast Neoplasms/metabolism, Wnt Signaling Pathway/drug effects, Clofazimine, Drug combination, Targeted therapy, Triple-negative breast cancer, Wnt signaling
Pubmed
Web of science
Create date
31/03/2019 14:21
Last modification date
17/09/2020 8:13
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