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

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 a...

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Autores principales:	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 Naitoh, Suresh V. Ambudkar, Michiaki Unno
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	ABCG2 inhibitor multidrug resistance phenylfurocoumarin ABC transporter chemosensitivity Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/1ac156644a834f0e808c9d18532a482d
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spelling	oai:doaj.org-article:1ac156644a834f0e808c9d18532a482d2021-11-25T17:57:18ZA Phenylfurocoumarin Derivative Reverses ABCG2-Mediated Multidrug Resistance In Vitro and In Vivo10.3390/ijms2222125021422-00671661-6596https://doaj.org/article/1ac156644a834f0e808c9d18532a482d2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12502https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067The 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 IC<sub>50</sub> 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.Shoji KokuboShinobu OhnumaMegumi MurakamiHaruhisa KikuchiShota FunayamaHideyuki SuzukiTaiki KajiwaraAkihiro YamamuraHideaki KarasawaNorihiko SugisawaKosuke OhsawaKuniyuki KanoJunken AokiTakayuki DoiTakeshi NaitohSuresh V. AmbudkarMichiaki UnnoMDPI AGarticleABCG2 inhibitormultidrug resistancephenylfurocoumarinABC transporterchemosensitivityBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12502, p 12502 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ABCG2 inhibitor multidrug resistance phenylfurocoumarin ABC transporter chemosensitivity Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	ABCG2 inhibitor multidrug resistance phenylfurocoumarin ABC transporter chemosensitivity Biology (General) QH301-705.5 Chemistry QD1-999 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 Naitoh Suresh V. Ambudkar Michiaki Unno A Phenylfurocoumarin Derivative Reverses ABCG2-Mediated Multidrug Resistance In Vitro and In Vivo
description	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 IC<sub>50</sub> 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.
format	article
author	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 Naitoh Suresh V. Ambudkar Michiaki Unno
author_facet	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 Naitoh Suresh V. Ambudkar Michiaki Unno
author_sort	Shoji Kokubo
title	A Phenylfurocoumarin Derivative Reverses ABCG2-Mediated Multidrug Resistance In Vitro and In Vivo
title_short	A Phenylfurocoumarin Derivative Reverses ABCG2-Mediated Multidrug Resistance In Vitro and In Vivo
title_full	A Phenylfurocoumarin Derivative Reverses ABCG2-Mediated Multidrug Resistance In Vitro and In Vivo
title_fullStr	A Phenylfurocoumarin Derivative Reverses ABCG2-Mediated Multidrug Resistance In Vitro and In Vivo
title_full_unstemmed	A Phenylfurocoumarin Derivative Reverses ABCG2-Mediated Multidrug Resistance In Vitro and In Vivo
title_sort	phenylfurocoumarin derivative reverses abcg2-mediated multidrug resistance in vitro and in vivo
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/1ac156644a834f0e808c9d18532a482d
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A Phenylfurocoumarin Derivative Reverses ABCG2-Mediated Multidrug Resistance In Vitro and In Vivo

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