Drug repurposing screening identifies bortezomib and panobinostat as drugs targeting cancer associated fibroblasts (CAFs) by synergistic induction of apoptosis
Summary Cancer associated fibroblasts (CAFs) are the most abundant components of cancer-microenvironment. They play important roles in cancer initiation, progression, and metastasis. In addition, CAFs can confer drug-resistance to cancer cells. Considering their pro-tumorigenic roles, it is recommen...
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Published in | Investigational new drugs Vol. 36; no. 4; pp. 545 - 560 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Springer US
01.08.2018
Springer Nature B.V |
Subjects | |
Online Access | Get full text |
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Summary: | Summary
Cancer associated fibroblasts (CAFs) are the most abundant components of cancer-microenvironment. They play important roles in cancer initiation, progression, and metastasis. In addition, CAFs can confer drug-resistance to cancer cells. Considering their pro-tumorigenic roles, it is recommended to remove CAFs to prevent cancer recurrence after chemotherapy. Despite their clinical significance, few anti-CAF drugs have been developed. The objective of this study was to find a drug that could suppress the viability of patient-derived CAFs through repurposed screening of 51 drugs that were in clinical trials or received FDA approval. As a result, bortezomib (BTZ), carfilzomib (CFZ), and panobinostat (PST) were identified as anti-CAF drug candidates. It was confirmed that BTZ and PST could decrease the viability of various patients derived CAFs through inducing of caspase-3 mediated apoptosis. Interestingly, combination therapy with BTZ and PST showed better efficacy of inhibiting CAFs than single treatment. The synergistic effect between BTZ and PST on viability of CAFs was observed both
in vitro
CAF culture and
in vivo
mouse model. Furthermore, combination therapy with BTZ/PST and conventional anticancer compound docetaxel strongly inhibited tumor growth in xenografts of mouse breast cancer cells with mouse CAFs. In conclusion, our present study revealed that BTZ and PST could significantly reduce the viability of CAFs. Therefore, a combination therapy with BTZ/PST and anticancer drugs might be considered as a new rational for the development of anticancer therapy. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0167-6997 1573-0646 |
DOI: | 10.1007/s10637-017-0547-8 |