Cinnamophilin overcomes cancer multi-drug resistance via allosterically modulating human P-glycoprotein on both drug binding sites and ATPase binding sites

Cancer multi-drug resistance (MDR) caused by P-glycoprotein (P-gp) efflux is a critical unresolved clinical concern. The present study analyzed the effect of cinnamophilin on P-gp inhibition and MDR reversion. The effect of cinnamophilin on P-gp was investigated through drug efflux assay, ATPase ass...

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Autores principales:	Yu-Ning Teng, Bo-Hau Huang, Shih-Ya Huang, I-Ting Wu, Tian-Shung Wu, Tsui-Er Lee, Chin-Chuan Hung
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	ATP-binding cassette Cancer multi-drug resistance Cinnamophilin Cinnamomum philippinense Natural product P-glycoprotein Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/8de39f178a3c42a8ad05755b13c86a09
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spelling	oai:doaj.org-article:8de39f178a3c42a8ad05755b13c86a092021-11-14T04:30:26ZCinnamophilin overcomes cancer multi-drug resistance via allosterically modulating human P-glycoprotein on both drug binding sites and ATPase binding sites0753-332210.1016/j.biopha.2021.112379https://doaj.org/article/8de39f178a3c42a8ad05755b13c86a092021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S075333222101163Xhttps://doaj.org/toc/0753-3322Cancer multi-drug resistance (MDR) caused by P-glycoprotein (P-gp) efflux is a critical unresolved clinical concern. The present study analyzed the effect of cinnamophilin on P-gp inhibition and MDR reversion. The effect of cinnamophilin on P-gp was investigated through drug efflux assay, ATPase assay, MDR1 shift assay, and molecular docking. The cancer MDR-reversing ability and mechanisms were analyzed through cytotoxicity and combination index (CI), cell cycle, and apoptosis experiments. P-gp efflux function was significantly inhibited by cinnamophilin without influencing the drug’s expression or conformation. Cinnamophilin uncompetitively inhibited the efflux of doxorubicin and rhodamine 123 and exhibited a distinct binding behavior compared with verapamil, the P-gp standard inhibitor. The half maximal inhibitory concentration of cinnamophilin for doxorubicin and rhodamine 123 efflux was 12.47 and 11.59 μM, respectively. In regard to P-gp energy consumption, verapamil-stimulated ATPase activity was further enhanced by cinnamophilin at concentrations of 0.1, 1, 10, and 20 μM. In terms of MDR reversion, cinnamophilin demonstrated synergistic cytotoxic effects when combined with docetaxel, vincristine, or paclitaxel. The CI was < 0.7 in all experimental combination treatments. The present study showed that cinnamophilin possesses P-gp-modulating effects and cancer MDR resensitizing ability.Yu-Ning TengBo-Hau HuangShih-Ya HuangI-Ting WuTian-Shung WuTsui-Er LeeChin-Chuan HungElsevierarticleATP-binding cassetteCancer multi-drug resistanceCinnamophilinCinnamomum philippinenseNatural productP-glycoproteinTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 144, Iss , Pp 112379- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ATP-binding cassette Cancer multi-drug resistance Cinnamophilin Cinnamomum philippinense Natural product P-glycoprotein Therapeutics. Pharmacology RM1-950
spellingShingle	ATP-binding cassette Cancer multi-drug resistance Cinnamophilin Cinnamomum philippinense Natural product P-glycoprotein Therapeutics. Pharmacology RM1-950 Yu-Ning Teng Bo-Hau Huang Shih-Ya Huang I-Ting Wu Tian-Shung Wu Tsui-Er Lee Chin-Chuan Hung Cinnamophilin overcomes cancer multi-drug resistance via allosterically modulating human P-glycoprotein on both drug binding sites and ATPase binding sites
description	Cancer multi-drug resistance (MDR) caused by P-glycoprotein (P-gp) efflux is a critical unresolved clinical concern. The present study analyzed the effect of cinnamophilin on P-gp inhibition and MDR reversion. The effect of cinnamophilin on P-gp was investigated through drug efflux assay, ATPase assay, MDR1 shift assay, and molecular docking. The cancer MDR-reversing ability and mechanisms were analyzed through cytotoxicity and combination index (CI), cell cycle, and apoptosis experiments. P-gp efflux function was significantly inhibited by cinnamophilin without influencing the drug’s expression or conformation. Cinnamophilin uncompetitively inhibited the efflux of doxorubicin and rhodamine 123 and exhibited a distinct binding behavior compared with verapamil, the P-gp standard inhibitor. The half maximal inhibitory concentration of cinnamophilin for doxorubicin and rhodamine 123 efflux was 12.47 and 11.59 μM, respectively. In regard to P-gp energy consumption, verapamil-stimulated ATPase activity was further enhanced by cinnamophilin at concentrations of 0.1, 1, 10, and 20 μM. In terms of MDR reversion, cinnamophilin demonstrated synergistic cytotoxic effects when combined with docetaxel, vincristine, or paclitaxel. The CI was < 0.7 in all experimental combination treatments. The present study showed that cinnamophilin possesses P-gp-modulating effects and cancer MDR resensitizing ability.
format	article
author	Yu-Ning Teng Bo-Hau Huang Shih-Ya Huang I-Ting Wu Tian-Shung Wu Tsui-Er Lee Chin-Chuan Hung
author_facet	Yu-Ning Teng Bo-Hau Huang Shih-Ya Huang I-Ting Wu Tian-Shung Wu Tsui-Er Lee Chin-Chuan Hung
author_sort	Yu-Ning Teng
title	Cinnamophilin overcomes cancer multi-drug resistance via allosterically modulating human P-glycoprotein on both drug binding sites and ATPase binding sites
title_short	Cinnamophilin overcomes cancer multi-drug resistance via allosterically modulating human P-glycoprotein on both drug binding sites and ATPase binding sites
title_full	Cinnamophilin overcomes cancer multi-drug resistance via allosterically modulating human P-glycoprotein on both drug binding sites and ATPase binding sites
title_fullStr	Cinnamophilin overcomes cancer multi-drug resistance via allosterically modulating human P-glycoprotein on both drug binding sites and ATPase binding sites
title_full_unstemmed	Cinnamophilin overcomes cancer multi-drug resistance via allosterically modulating human P-glycoprotein on both drug binding sites and ATPase binding sites
title_sort	cinnamophilin overcomes cancer multi-drug resistance via allosterically modulating human p-glycoprotein on both drug binding sites and atpase binding sites
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/8de39f178a3c42a8ad05755b13c86a09
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Cinnamophilin overcomes cancer multi-drug resistance via allosterically modulating human P-glycoprotein on both drug binding sites and ATPase binding sites

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