Regorafenib antagonizes BCRP-mediated multidrug resistance in colon cancer.
ATP Binding Cassette Transporter, Subfamily G, Member 2
/ agonists
Animals
Antineoplastic Agents
/ chemistry
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Binding Sites
Cell Line, Tumor
Colonic Neoplasms
/ drug therapy
Dose-Response Relationship, Drug
Drug Resistance, Multiple
/ drug effects
Drug Resistance, Neoplasm
/ drug effects
Drug Synergism
Humans
Male
Mice, Nude
Mitoxantrone
/ pharmacology
Molecular Docking Simulation
Molecular Dynamics Simulation
Neoplasm Proteins
/ agonists
Phenylurea Compounds
/ chemistry
Protein Binding
Protein Conformation
Pyridines
/ chemistry
Topotecan
/ pharmacology
Tumor Burden
/ drug effects
Xenograft Model Antitumor Assays
Combination chemotherapy with regorafenib
Reversal of multidrug resistance
Synergy
Journal
Cancer letters
ISSN: 1872-7980
Titre abrégé: Cancer Lett
Pays: Ireland
ID NLM: 7600053
Informations de publication
Date de publication:
01 02 2019
01 02 2019
Historique:
received:
06
07
2018
revised:
17
10
2018
accepted:
24
10
2018
pubmed:
6
11
2018
medline:
5
11
2019
entrez:
6
11
2018
Statut:
ppublish
Résumé
Overexpression of breast cancer resistance protein (BCRP) has been shown to produce multidrug resistance (MDR) in colon cancer, leading to major obstacles for chemotherapy. In this study, we evaluated the effect of regorafenib, an oral multi-kinase inhibitor, in inhibiting BCRP-mediated MDR in silico, in vitro and in vivo. We found that regorafenib significantly sensitized MDR colon cancer cells to BCRP substrates by increasing their intracellular accumulation. There are no significant changes in the expression level or the subcellular distribution of BCRP in the cells exposed to regorafenib. Investigation of the mechanism revealed that regorafenib stimulated BCRP ATPase activity. Our induced-fit docking and molecular dynamics simulations suggested the existence of a strong and stable interaction between regorafenib and the transmembrane domain of human crystalized BCRP. In vivo tumor xenograft study revealed that the combination of regorafenib and topotecan exhibited synergistic effects on mitoxantrone-resistant S1-M1-80 xenograft tumors. In conclusion, our studies indicate that regorafenib would be beneficial in combating MDR in colon cancer.
Identifiants
pubmed: 30392788
pii: S0304-3835(18)30647-5
doi: 10.1016/j.canlet.2018.10.032
pmc: PMC8148022
mid: NIHMS1693389
pii:
doi:
Substances chimiques
ABCG2 protein, human
0
ATP Binding Cassette Transporter, Subfamily G, Member 2
0
Antineoplastic Agents
0
Neoplasm Proteins
0
Phenylurea Compounds
0
Pyridines
0
regorafenib
24T2A1DOYB
Topotecan
7M7YKX2N15
Mitoxantrone
BZ114NVM5P
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
104-112Subventions
Organisme : NCI NIH HHS
ID : R15 CA143701
Pays : United States
Organisme : NIGMS NIH HHS
ID : R15 GM116043
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 BC010030
Pays : United States
Informations de copyright
Copyright © 2018 Elsevier B.V. All rights reserved.
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