RRC ID 52571
Author Lee HM, Lee E, Yeo SY, Shin S, Park HK, Nam DH, Kim SH.
Title Drug repurposing screening identifies bortezomib and panobinostat as drugs targeting cancer associated fibroblasts (CAFs) by synergistic induction of apoptosis.
Journal Invest New Drugs
Abstract 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.
Volume 36(4)
Pages 545-560
Published 2018-8
DOI 10.1007/s10637-017-0547-8
PII 10.1007/s10637-017-0547-8
PMID 29349597
MeSH Animals Apoptosis / drug effects* Bortezomib / pharmacology* Cancer-Associated Fibroblasts / drug effects* Cell Line Cell Line, Tumor Drug Repositioning / methods Drug Synergism Early Detection of Cancer / methods Female Humans Mice Mice, Inbred BALB C Mice, Nude Neoplasm Recurrence, Local / drug therapy Oligopeptides / pharmacology Panobinostat / pharmacology*
IF 2.663
Human and Animal Cells TE-11(RCB2100)