A Phenylfurocoumarin Derivative Reverses ABCG2-Mediated Multidrug Resistance In Vitro and In Vivo

Autor: Shota Funayama, Norihiko Sugisawa, Shinobu Ohnuma, Kosuke Ohsawa, Akihiro Yamamura, Kuniyuki Kano, Megumi Murakami, Suresh V. Ambudkar, Takeshi Naitoh, Hideyuki Suzuki, Junken Aoki, Michiaki Unno, Shoji Kokubo, Takayuki Doi, Haruhisa Kikuchi, Hideaki Karasawa, Taiki Kajiwara
Rok vydání: 2021
Předmět:
Chlorophyll
Abcg2
phenylfurocoumarin
Pharmacology
Chemical library
Mice
chemistry.chemical_compound
ABCG2 inhibitor
Furocoumarins
Neoplasms
ATP Binding Cassette Transporter
Subfamily G
Member 2
Biology (General)
Spectroscopy
biology
Chemistry
General Medicine
Flow Cytometry
Drug Resistance
Multiple
Neoplasm Proteins
Computer Science Applications
chemosensitivity
embryonic structures
Heterografts
ABC transporter
Efflux
QH301-705.5
Antineoplastic Agents
Irinotecan
Article
Catalysis
Inorganic Chemistry
multidrug resistance
In vivo
medicine
Animals
Humans
Physical and Theoretical Chemistry
QD1-999
Molecular Biology
Cell Proliferation
Organic Chemistry
Cancer
Biological Transport
HCT116 Cells
medicine.disease
In vitro
High-Throughput Screening Assays
Multiple drug resistance
Drug Resistance
Neoplasm
Cancer cell
biology.protein
sense organs
Zdroj: International Journal of Molecular Sciences
International Journal of Molecular Sciences, Vol 22, Iss 12502, p 12502 (2021)
Volume 22
Issue 22
ISSN: 1422-0067
DOI: 10.3390/ijms222212502
Popis: The ATP-binding cassette subfamily G member 2 (ABCG2) transporter is involved in the development of multidrug resistance in cancer patients. Many inhibitors of ABCG2 have been reported to enhance the chemosensitivity of cancer cells. However, none of these inhibitors are being used clinically. The aim of this study was to identify novel ABCG2 inhibitors by high-throughput screening of a chemical library. Among the 5812 compounds in the library, 23 compounds were selected in the first screening, using a fluorescent plate reader-based pheophorbide a (PhA) efflux assay. Thereafter, to validate these compounds, a flow cytometry-based PhA efflux assay was performed and 16 compounds were identified as potential inhibitors. A cytotoxic assay was then performed to assess the effect these 16 compounds had on ABCG2-mediated chemosensitivity. We found that the phenylfurocoumarin derivative (R)-9-(3,4-dimethoxyphenyl)-4-((3,3-dimethyloxiran-2-yl)methoxy)-7H-furo [3,2-g]chromen-7-one (PFC) significantly decreased the IC50 of SN-38 in HCT-116/BCRP colon cancer cells. In addition, PFC stimulated ABCG2-mediated ATP hydrolysis, suggesting that this compound interacts with the substrate-binding site of ABCG2. Furthermore, PFC reversed the resistance to irinotecan without causing toxicity in the ABCG2-overexpressing HCT-116/BCRP cell xenograft mouse model. In conclusion, PFC is a novel inhibitor of ABCG2 and has promise as a therapeutic to overcome ABCG2-mediated MDR, to improve the efficiency of cancer chemotherapy.
Databáze: OpenAIRE
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