A phenylfurocoumarin derivative reverses ABCG2-mediated multidrug resistance in vitro and in vivo

Shoji Kokubo, Shinobu Ohnuma, Megumi Murakami, Haruhisa Kikuchi, Shota Funayama, Hideyuki Suzuki, Taiki Kajiwara, Akihiro Yamamura, Hideaki Karasawa, Norihiko Sugisawa, Kosuke Ohsawa, Kuniyuki Kano, Junken Aoki, Takayuki Doi, Takeshi Naito, Suresh V. Ambudkar, Michiaki Unno

研究成果: Article査読

2 被引用数 (Scopus)


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.

ジャーナルInternational journal of molecular sciences
出版ステータスPublished - 2021 11月 1

ASJC Scopus subject areas

  • 触媒
  • 分子生物学
  • 分光学
  • コンピュータ サイエンスの応用
  • 物理化学および理論化学
  • 有機化学
  • 無機化学


「A phenylfurocoumarin derivative reverses ABCG2-mediated multidrug resistance in vitro and in vivo」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。