The Antileukemic Effect of Xestoquinone, A Marine-Derived Polycyclic Quinone-Type Metabolite, Is Mediated through ROS-Induced Inhibition of HSP-90

Xestoquinone is a polycyclic quinone-type metabolite with a reported antitumor effect. We tested the cytotoxic activity of xestoquinone on a series of hematological cancer cell lines. The antileukemic effect of xestoquinone was evaluated in vitro and in vivo. This marine metabolite suppressed the pr...

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Autores principales:	Kuan-Chih Wang, Mei-Chin Lu, Kai-Cheng Hsu, Mohamed El-Shazly, Shou-Ping Shih, Ssu-Ting Lien, Fu-Wen Kuo, Shyh-Chyun Yang, Chun-Lin Chen, Yu-Chen S. H. Yang
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	polycyclic quinone xestoquinone apoptosis anticancer topoisomerase reactive oxygen species (ROS) Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/0f779598f48a428d996bf6389ff62567
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spelling	oai:doaj.org-article:0f779598f48a428d996bf6389ff625672021-11-25T18:29:21ZThe Antileukemic Effect of Xestoquinone, A Marine-Derived Polycyclic Quinone-Type Metabolite, Is Mediated through ROS-Induced Inhibition of HSP-9010.3390/molecules262270371420-3049https://doaj.org/article/0f779598f48a428d996bf6389ff625672021-11-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/22/7037https://doaj.org/toc/1420-3049Xestoquinone is a polycyclic quinone-type metabolite with a reported antitumor effect. We tested the cytotoxic activity of xestoquinone on a series of hematological cancer cell lines. The antileukemic effect of xestoquinone was evaluated in vitro and in vivo. This marine metabolite suppressed the proliferation of Molt-4, K562, and Sup-T1 cells with IC<sub>50</sub> values of 2.95 ± 0.21, 6.22 ± 0.21, and 8.58 ± 0.60 µM, respectively, as demonstrated by MTT assay. In the cell-free system, it inhibited the activity of topoisomerase I (Topo I) and II (Topo II) by 50% after treatment with 0.235 and 0.094 μM, respectively. The flow cytometric analysis indicated that the cytotoxic effect of xestoquinone was mediated through the induction of multiple apoptotic pathways in Molt-4 cells. The pretreatment of Molt-4 cells with N-acetyl cysteine (NAC) diminished the disruption of the mitochondrial membrane potential (MMP) and apoptosis, as well as retaining the expression of both Topo I and II. In the nude mice xenograft model, the administration of xestoquinone (1 μg/g) significantly attenuated tumor growth by 31.2% compared with the solvent control. Molecular docking, Western blotting, and thermal shift assay verified the catalytic inhibitory activity of xestoquinone by high binding affinity to HSP-90 and Topo I/II. Our findings indicated that xestoquinone targeted leukemia cancer cells through multiple pathways, suggesting its potential application as an antileukemic drug lead.Kuan-Chih WangMei-Chin LuKai-Cheng HsuMohamed El-ShazlyShou-Ping ShihSsu-Ting LienFu-Wen KuoShyh-Chyun YangChun-Lin ChenYu-Chen S. H. YangMDPI AGarticlepolycyclic quinonexestoquinoneapoptosisanticancertopoisomerasereactive oxygen species (ROS)Organic chemistryQD241-441ENMolecules, Vol 26, Iss 7037, p 7037 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	polycyclic quinone xestoquinone apoptosis anticancer topoisomerase reactive oxygen species (ROS) Organic chemistry QD241-441
spellingShingle	polycyclic quinone xestoquinone apoptosis anticancer topoisomerase reactive oxygen species (ROS) Organic chemistry QD241-441 Kuan-Chih Wang Mei-Chin Lu Kai-Cheng Hsu Mohamed El-Shazly Shou-Ping Shih Ssu-Ting Lien Fu-Wen Kuo Shyh-Chyun Yang Chun-Lin Chen Yu-Chen S. H. Yang The Antileukemic Effect of Xestoquinone, A Marine-Derived Polycyclic Quinone-Type Metabolite, Is Mediated through ROS-Induced Inhibition of HSP-90
description	Xestoquinone is a polycyclic quinone-type metabolite with a reported antitumor effect. We tested the cytotoxic activity of xestoquinone on a series of hematological cancer cell lines. The antileukemic effect of xestoquinone was evaluated in vitro and in vivo. This marine metabolite suppressed the proliferation of Molt-4, K562, and Sup-T1 cells with IC<sub>50</sub> values of 2.95 ± 0.21, 6.22 ± 0.21, and 8.58 ± 0.60 µM, respectively, as demonstrated by MTT assay. In the cell-free system, it inhibited the activity of topoisomerase I (Topo I) and II (Topo II) by 50% after treatment with 0.235 and 0.094 μM, respectively. The flow cytometric analysis indicated that the cytotoxic effect of xestoquinone was mediated through the induction of multiple apoptotic pathways in Molt-4 cells. The pretreatment of Molt-4 cells with N-acetyl cysteine (NAC) diminished the disruption of the mitochondrial membrane potential (MMP) and apoptosis, as well as retaining the expression of both Topo I and II. In the nude mice xenograft model, the administration of xestoquinone (1 μg/g) significantly attenuated tumor growth by 31.2% compared with the solvent control. Molecular docking, Western blotting, and thermal shift assay verified the catalytic inhibitory activity of xestoquinone by high binding affinity to HSP-90 and Topo I/II. Our findings indicated that xestoquinone targeted leukemia cancer cells through multiple pathways, suggesting its potential application as an antileukemic drug lead.
format	article
author	Kuan-Chih Wang Mei-Chin Lu Kai-Cheng Hsu Mohamed El-Shazly Shou-Ping Shih Ssu-Ting Lien Fu-Wen Kuo Shyh-Chyun Yang Chun-Lin Chen Yu-Chen S. H. Yang
author_facet	Kuan-Chih Wang Mei-Chin Lu Kai-Cheng Hsu Mohamed El-Shazly Shou-Ping Shih Ssu-Ting Lien Fu-Wen Kuo Shyh-Chyun Yang Chun-Lin Chen Yu-Chen S. H. Yang
author_sort	Kuan-Chih Wang
title	The Antileukemic Effect of Xestoquinone, A Marine-Derived Polycyclic Quinone-Type Metabolite, Is Mediated through ROS-Induced Inhibition of HSP-90
title_short	The Antileukemic Effect of Xestoquinone, A Marine-Derived Polycyclic Quinone-Type Metabolite, Is Mediated through ROS-Induced Inhibition of HSP-90
title_full	The Antileukemic Effect of Xestoquinone, A Marine-Derived Polycyclic Quinone-Type Metabolite, Is Mediated through ROS-Induced Inhibition of HSP-90
title_fullStr	The Antileukemic Effect of Xestoquinone, A Marine-Derived Polycyclic Quinone-Type Metabolite, Is Mediated through ROS-Induced Inhibition of HSP-90
title_full_unstemmed	The Antileukemic Effect of Xestoquinone, A Marine-Derived Polycyclic Quinone-Type Metabolite, Is Mediated through ROS-Induced Inhibition of HSP-90
title_sort	antileukemic effect of xestoquinone, a marine-derived polycyclic quinone-type metabolite, is mediated through ros-induced inhibition of hsp-90
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/0f779598f48a428d996bf6389ff62567
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The Antileukemic Effect of Xestoquinone, A Marine-Derived Polycyclic Quinone-Type Metabolite, Is Mediated through ROS-Induced Inhibition of HSP-90

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