TY - JOUR
T1 - A phenylfurocoumarin derivative reverses ABCG2-mediated multidrug resistance in vitro and in vivo
AU - Kokubo, Shoji
AU - Ohnuma, Shinobu
AU - Murakami, Megumi
AU - Kikuchi, Haruhisa
AU - Funayama, Shota
AU - Suzuki, Hideyuki
AU - Kajiwara, Taiki
AU - Yamamura, Akihiro
AU - Karasawa, Hideaki
AU - Sugisawa, Norihiko
AU - Ohsawa, Kosuke
AU - Kano, Kuniyuki
AU - Aoki, Junken
AU - Doi, Takayuki
AU - Naitoh, Takeshi
AU - Ambudkar, Suresh V.
AU - Unno, Michiaki
N1 - Funding Information:
Funding: The work of M.M. and S.V.A was supported by the Intramural Research Program of National Institutes of Health, National Cancer Institute, Center for Cancer Research. This work was also partially supported by the Platform Project for Supporting in Drug Discovery and Life Science Research from AMED under Grant Number JP21am0101095 (representative: prof. Masayuki Yamamoto).
Publisher Copyright:
© 2021 by the author. Licensee MDPI, Basel, Switzerland.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - 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 re-ported 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-dime-thyloxiran-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. Fur-thermore, PFC reversed the resistance to irinotecan without causing toxicity in the ABCG2-overex-pressing 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.
AB - 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 re-ported 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-dime-thyloxiran-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. Fur-thermore, PFC reversed the resistance to irinotecan without causing toxicity in the ABCG2-overex-pressing 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.
KW - ABC transporter
KW - ABCG2 inhibitor
KW - Chemosensitivity
KW - Multidrug resistance
KW - Phenylfurocoumarin
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U2 - 10.3390/ijms222212502
DO - 10.3390/ijms222212502
M3 - Article
C2 - 34830383
AN - SCOPUS:85119289051
SN - 1661-6596
VL - 22
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 22
M1 - 12502
ER -
