A novel epoxypropoxy flavonoid derivative and topoisomerase II inhibitor, MHY336, induces apoptosis in prostate cancer cells

Here, we reported the synthesis of a novel topoisomerase II inhibitor, MHY336, which that has strong topoisomerase-mediated anticancer activity but fewer side effects than other topoisomerase II inhibitors. The catalytic activity of MHY336 on the topoisomerase II enzyme was the same as that of the e...

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Veröffentlicht in:European journal of pharmacology 2011-05, Vol.658 (2), p.98-107
Hauptverfasser: Patra, Nabanita, De, Umasankar, Kang, Jin-Ah, Kim, Ji Mim, Ahn, Mee Young, Lee, Jaewon, Jung, Jee H., Chung, Hae Young, Moon, Hyung Ryong, Kim, Hyung Sik
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container_issue 2
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container_title European journal of pharmacology
container_volume 658
creator Patra, Nabanita
De, Umasankar
Kang, Jin-Ah
Kim, Ji Mim
Ahn, Mee Young
Lee, Jaewon
Jung, Jee H.
Chung, Hae Young
Moon, Hyung Ryong
Kim, Hyung Sik
description Here, we reported the synthesis of a novel topoisomerase II inhibitor, MHY336, which that has strong topoisomerase-mediated anticancer activity but fewer side effects than other topoisomerase II inhibitors. The catalytic activity of MHY336 on the topoisomerase II enzyme was the same as that of the etoposide. In a cell-free system, MHY336 exhibited a potent activity on scavenging of reactive oxygen species against 3-morpholinosydnonimine hydrochloride (SIN-1)-induced oxidative stress. An in vitro cell-based assay demonstrated that MHY336 significantly inhibited the proliferation of three prostate cancer cell lines, LNCaP, PC-3, and DU145 cells. Notably, the cytotoxicity of MHY336 was more potent in LNCaP cells (IC 50 = 1.39 μM) than in DU145 (IC 50 = 2.94 μM) and PC3 cells (IC 50 = 3.72 μM). Furthermore, MHY336 treatment induced similar levels of cytotoxicity compared to doxorubicin treatment (IC 50 = 1.55 μM) in LNCap cells. Also, MHY336 significantly down-regulated topoisomerase II alpha expression and up-regulated p53 expression in LNCaP cells (wild-type p53), whereas it up-regulated the topoisomerase II alpha protein in both DU145 and PC3 cells (p53 mutated or deleted). MHY336 induced G2/M or S phase arrest in LNCaP cells through a well-documented topoisomerase II-dependent mechanism. Further studies using Annexin V-FITC binding assay, DAPI staining, and Western blot analyses illustrated that MHY336 markedly induced apoptotic cell death via the mitochondria-mediated intrinsic pathway in LNCaP cells. These results suggest that MHY336 is an attractive chemotherapeutic agent because of its topoisomerase II-mediated anti-tumour activity in human prostate cancer.
doi_str_mv 10.1016/j.ejphar.2011.02.015
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The catalytic activity of MHY336 on the topoisomerase II enzyme was the same as that of the etoposide. In a cell-free system, MHY336 exhibited a potent activity on scavenging of reactive oxygen species against 3-morpholinosydnonimine hydrochloride (SIN-1)-induced oxidative stress. An in vitro cell-based assay demonstrated that MHY336 significantly inhibited the proliferation of three prostate cancer cell lines, LNCaP, PC-3, and DU145 cells. Notably, the cytotoxicity of MHY336 was more potent in LNCaP cells (IC 50 = 1.39 μM) than in DU145 (IC 50 = 2.94 μM) and PC3 cells (IC 50 = 3.72 μM). Furthermore, MHY336 treatment induced similar levels of cytotoxicity compared to doxorubicin treatment (IC 50 = 1.55 μM) in LNCap cells. Also, MHY336 significantly down-regulated topoisomerase II alpha expression and up-regulated p53 expression in LNCaP cells (wild-type p53), whereas it up-regulated the topoisomerase II alpha protein in both DU145 and PC3 cells (p53 mutated or deleted). MHY336 induced G2/M or S phase arrest in LNCaP cells through a well-documented topoisomerase II-dependent mechanism. Further studies using Annexin V-FITC binding assay, DAPI staining, and Western blot analyses illustrated that MHY336 markedly induced apoptotic cell death via the mitochondria-mediated intrinsic pathway in LNCaP cells. These results suggest that MHY336 is an attractive chemotherapeutic agent because of its topoisomerase II-mediated anti-tumour activity in human prostate cancer.</description><identifier>ISSN: 0014-2999</identifier><identifier>EISSN: 1879-0712</identifier><identifier>DOI: 10.1016/j.ejphar.2011.02.015</identifier><identifier>PMID: 21376033</identifier><identifier>CODEN: EJPHAZ</identifier><language>eng</language><publisher>Amsterdam: Elsevier B.V</publisher><subject>adverse effects ; Annexins ; anticarcinogenic activity ; Antineoplastic Agents - chemical synthesis ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Apoptosis ; Apoptosis - drug effects ; Biocatalysis - drug effects ; Biological and medical sciences ; catalytic activity ; Cell Cycle - drug effects ; cell free system ; Cell Line, Tumor ; Cell Proliferation - drug effects ; cytotoxicity ; DNA topoisomerase (ATP-hydrolysing) ; DNA Topoisomerases, Type II - metabolism ; Down-Regulation - drug effects ; doxorubicin ; flavonoids ; Flavonoids - chemical synthesis ; Flavonoids - chemistry ; Flavonoids - pharmacology ; Free Radical Scavengers - chemical synthesis ; Free Radical Scavengers - chemistry ; Free Radical Scavengers - pharmacology ; Gynecology. Andrology. Obstetrics ; Humans ; interphase ; Male ; Male genital diseases ; Medical sciences ; MHY336 ; Molsidomine - analogs &amp; derivatives ; Molsidomine - pharmacology ; Nephrology. Urinary tract diseases ; oxidative stress ; Oxidative Stress - drug effects ; p53 ; Pharmacology. Drug treatments ; Prostate cancer ; prostatic neoplasms ; Prostatic Neoplasms - metabolism ; Prostatic Neoplasms - pathology ; reactive oxygen species ; Reactive Oxygen Species - metabolism ; Topoisomerase II inhibitor ; Topoisomerase II Inhibitors - chemical synthesis ; Topoisomerase II Inhibitors - chemistry ; Topoisomerase II Inhibitors - pharmacology ; Tumor Suppressor Protein p53 - metabolism ; Tumors ; Tumors of the urinary system ; Up-Regulation - drug effects ; Urinary tract. Prostate gland ; Western blotting</subject><ispartof>European journal of pharmacology, 2011-05, Vol.658 (2), p.98-107</ispartof><rights>2011</rights><rights>2015 INIST-CNRS</rights><rights>Crown Copyright © 2011. 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The catalytic activity of MHY336 on the topoisomerase II enzyme was the same as that of the etoposide. In a cell-free system, MHY336 exhibited a potent activity on scavenging of reactive oxygen species against 3-morpholinosydnonimine hydrochloride (SIN-1)-induced oxidative stress. An in vitro cell-based assay demonstrated that MHY336 significantly inhibited the proliferation of three prostate cancer cell lines, LNCaP, PC-3, and DU145 cells. Notably, the cytotoxicity of MHY336 was more potent in LNCaP cells (IC 50 = 1.39 μM) than in DU145 (IC 50 = 2.94 μM) and PC3 cells (IC 50 = 3.72 μM). Furthermore, MHY336 treatment induced similar levels of cytotoxicity compared to doxorubicin treatment (IC 50 = 1.55 μM) in LNCap cells. Also, MHY336 significantly down-regulated topoisomerase II alpha expression and up-regulated p53 expression in LNCaP cells (wild-type p53), whereas it up-regulated the topoisomerase II alpha protein in both DU145 and PC3 cells (p53 mutated or deleted). MHY336 induced G2/M or S phase arrest in LNCaP cells through a well-documented topoisomerase II-dependent mechanism. Further studies using Annexin V-FITC binding assay, DAPI staining, and Western blot analyses illustrated that MHY336 markedly induced apoptotic cell death via the mitochondria-mediated intrinsic pathway in LNCaP cells. These results suggest that MHY336 is an attractive chemotherapeutic agent because of its topoisomerase II-mediated anti-tumour activity in human prostate cancer.</description><subject>adverse effects</subject><subject>Annexins</subject><subject>anticarcinogenic activity</subject><subject>Antineoplastic Agents - chemical synthesis</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Biocatalysis - drug effects</subject><subject>Biological and medical sciences</subject><subject>catalytic activity</subject><subject>Cell Cycle - drug effects</subject><subject>cell free system</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>cytotoxicity</subject><subject>DNA topoisomerase (ATP-hydrolysing)</subject><subject>DNA Topoisomerases, Type II - metabolism</subject><subject>Down-Regulation - drug effects</subject><subject>doxorubicin</subject><subject>flavonoids</subject><subject>Flavonoids - chemical synthesis</subject><subject>Flavonoids - chemistry</subject><subject>Flavonoids - pharmacology</subject><subject>Free Radical Scavengers - chemical synthesis</subject><subject>Free Radical Scavengers - chemistry</subject><subject>Free Radical Scavengers - pharmacology</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humans</subject><subject>interphase</subject><subject>Male</subject><subject>Male genital diseases</subject><subject>Medical sciences</subject><subject>MHY336</subject><subject>Molsidomine - analogs &amp; derivatives</subject><subject>Molsidomine - pharmacology</subject><subject>Nephrology. Urinary tract diseases</subject><subject>oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>p53</subject><subject>Pharmacology. Drug treatments</subject><subject>Prostate cancer</subject><subject>prostatic neoplasms</subject><subject>Prostatic Neoplasms - metabolism</subject><subject>Prostatic Neoplasms - pathology</subject><subject>reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Topoisomerase II inhibitor</subject><subject>Topoisomerase II Inhibitors - chemical synthesis</subject><subject>Topoisomerase II Inhibitors - chemistry</subject><subject>Topoisomerase II Inhibitors - pharmacology</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumors</subject><subject>Tumors of the urinary system</subject><subject>Up-Regulation - drug effects</subject><subject>Urinary tract. Prostate gland</subject><subject>Western blotting</subject><issn>0014-2999</issn><issn>1879-0712</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kctu1DAUhi0EotPCGyDwBsGiCb7FjjdIVVXoSEUsoAtWluML9SgTp3YmohIPj6MMsOvqSOd85_b_ALzCqMYI8w-72u3GO51qgjCuEakRbp6ADW6FrJDA5CnYIIRZRaSUJ-A05x1CqJGkeQ5OCKaCI0o34PcFHOLseujG-OthTHEJ0Pd6jkMMFlqXwqynMDuoBwunUg857l3S2cHtFobhLnRhiukcfrn-QSk_Lyl7MC5DPcZxijnkkoFlcp705KDRg3EJGtf3-QV45nWf3ctjPAO3n66-X15XN18_by8vbirDWDtV3BArkeEedRJZgwWVXtqmo9YwSpgkWHjcYa6xsALp1nrKSspj0fm2kZSegXfr3HLF_cHlSe1DXi7Qg4uHrNqiheSMk0K-f5TEjLeUtw0RBWUrasprOTmvxhT2Oj0ojNTikNqp1SG1OKQQUcWh0vb6uOHQ7Z391_TXkgK8PQI6G937VAQL-T_HEOdcLIPerJzXUemfqTC338qmptjMECbLMx9XwhVt5-CSyia4Ir8NyZlJ2Rgev_UPD426dA</recordid><startdate>20110511</startdate><enddate>20110511</enddate><creator>Patra, Nabanita</creator><creator>De, Umasankar</creator><creator>Kang, Jin-Ah</creator><creator>Kim, Ji Mim</creator><creator>Ahn, Mee Young</creator><creator>Lee, Jaewon</creator><creator>Jung, Jee H.</creator><creator>Chung, Hae Young</creator><creator>Moon, Hyung Ryong</creator><creator>Kim, Hyung Sik</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>FBQ</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>7X8</scope></search><sort><creationdate>20110511</creationdate><title>A novel epoxypropoxy flavonoid derivative and topoisomerase II inhibitor, MHY336, induces apoptosis in prostate cancer cells</title><author>Patra, Nabanita ; De, Umasankar ; Kang, Jin-Ah ; Kim, Ji Mim ; Ahn, Mee Young ; Lee, Jaewon ; Jung, Jee H. ; Chung, Hae Young ; Moon, Hyung Ryong ; Kim, Hyung Sik</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c448t-6c2d90c6f0b90dc1739f9d5b3dc43249217f1b16a17d70a8df3417ff17bf85933</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>adverse effects</topic><topic>Annexins</topic><topic>anticarcinogenic activity</topic><topic>Antineoplastic Agents - chemical synthesis</topic><topic>Antineoplastic Agents - chemistry</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Biocatalysis - drug effects</topic><topic>Biological and medical sciences</topic><topic>catalytic activity</topic><topic>Cell Cycle - drug effects</topic><topic>cell free system</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>cytotoxicity</topic><topic>DNA topoisomerase (ATP-hydrolysing)</topic><topic>DNA Topoisomerases, Type II - metabolism</topic><topic>Down-Regulation - drug effects</topic><topic>doxorubicin</topic><topic>flavonoids</topic><topic>Flavonoids - chemical synthesis</topic><topic>Flavonoids - chemistry</topic><topic>Flavonoids - pharmacology</topic><topic>Free Radical Scavengers - chemical synthesis</topic><topic>Free Radical Scavengers - chemistry</topic><topic>Free Radical Scavengers - pharmacology</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Humans</topic><topic>interphase</topic><topic>Male</topic><topic>Male genital diseases</topic><topic>Medical sciences</topic><topic>MHY336</topic><topic>Molsidomine - analogs &amp; derivatives</topic><topic>Molsidomine - pharmacology</topic><topic>Nephrology. Urinary tract diseases</topic><topic>oxidative stress</topic><topic>Oxidative Stress - drug effects</topic><topic>p53</topic><topic>Pharmacology. Drug treatments</topic><topic>Prostate cancer</topic><topic>prostatic neoplasms</topic><topic>Prostatic Neoplasms - metabolism</topic><topic>Prostatic Neoplasms - pathology</topic><topic>reactive oxygen species</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Topoisomerase II inhibitor</topic><topic>Topoisomerase II Inhibitors - chemical synthesis</topic><topic>Topoisomerase II Inhibitors - chemistry</topic><topic>Topoisomerase II Inhibitors - pharmacology</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumors</topic><topic>Tumors of the urinary system</topic><topic>Up-Regulation - drug effects</topic><topic>Urinary tract. Prostate gland</topic><topic>Western blotting</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Patra, Nabanita</creatorcontrib><creatorcontrib>De, Umasankar</creatorcontrib><creatorcontrib>Kang, Jin-Ah</creatorcontrib><creatorcontrib>Kim, Ji Mim</creatorcontrib><creatorcontrib>Ahn, Mee Young</creatorcontrib><creatorcontrib>Lee, Jaewon</creatorcontrib><creatorcontrib>Jung, Jee H.</creatorcontrib><creatorcontrib>Chung, Hae Young</creatorcontrib><creatorcontrib>Moon, Hyung Ryong</creatorcontrib><creatorcontrib>Kim, Hyung Sik</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Patra, Nabanita</au><au>De, Umasankar</au><au>Kang, Jin-Ah</au><au>Kim, Ji Mim</au><au>Ahn, Mee Young</au><au>Lee, Jaewon</au><au>Jung, Jee H.</au><au>Chung, Hae Young</au><au>Moon, Hyung Ryong</au><au>Kim, Hyung Sik</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A novel epoxypropoxy flavonoid derivative and topoisomerase II inhibitor, MHY336, induces apoptosis in prostate cancer cells</atitle><jtitle>European journal of pharmacology</jtitle><addtitle>Eur J Pharmacol</addtitle><date>2011-05-11</date><risdate>2011</risdate><volume>658</volume><issue>2</issue><spage>98</spage><epage>107</epage><pages>98-107</pages><issn>0014-2999</issn><eissn>1879-0712</eissn><coden>EJPHAZ</coden><abstract>Here, we reported the synthesis of a novel topoisomerase II inhibitor, MHY336, which that has strong topoisomerase-mediated anticancer activity but fewer side effects than other topoisomerase II inhibitors. The catalytic activity of MHY336 on the topoisomerase II enzyme was the same as that of the etoposide. In a cell-free system, MHY336 exhibited a potent activity on scavenging of reactive oxygen species against 3-morpholinosydnonimine hydrochloride (SIN-1)-induced oxidative stress. An in vitro cell-based assay demonstrated that MHY336 significantly inhibited the proliferation of three prostate cancer cell lines, LNCaP, PC-3, and DU145 cells. Notably, the cytotoxicity of MHY336 was more potent in LNCaP cells (IC 50 = 1.39 μM) than in DU145 (IC 50 = 2.94 μM) and PC3 cells (IC 50 = 3.72 μM). Furthermore, MHY336 treatment induced similar levels of cytotoxicity compared to doxorubicin treatment (IC 50 = 1.55 μM) in LNCap cells. Also, MHY336 significantly down-regulated topoisomerase II alpha expression and up-regulated p53 expression in LNCaP cells (wild-type p53), whereas it up-regulated the topoisomerase II alpha protein in both DU145 and PC3 cells (p53 mutated or deleted). MHY336 induced G2/M or S phase arrest in LNCaP cells through a well-documented topoisomerase II-dependent mechanism. Further studies using Annexin V-FITC binding assay, DAPI staining, and Western blot analyses illustrated that MHY336 markedly induced apoptotic cell death via the mitochondria-mediated intrinsic pathway in LNCaP cells. These results suggest that MHY336 is an attractive chemotherapeutic agent because of its topoisomerase II-mediated anti-tumour activity in human prostate cancer.</abstract><cop>Amsterdam</cop><pub>Elsevier B.V</pub><pmid>21376033</pmid><doi>10.1016/j.ejphar.2011.02.015</doi><tpages>10</tpages></addata></record>
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identifier ISSN: 0014-2999
ispartof European journal of pharmacology, 2011-05, Vol.658 (2), p.98-107
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subjects adverse effects
Annexins
anticarcinogenic activity
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis - drug effects
Biocatalysis - drug effects
Biological and medical sciences
catalytic activity
Cell Cycle - drug effects
cell free system
Cell Line, Tumor
Cell Proliferation - drug effects
cytotoxicity
DNA topoisomerase (ATP-hydrolysing)
DNA Topoisomerases, Type II - metabolism
Down-Regulation - drug effects
doxorubicin
flavonoids
Flavonoids - chemical synthesis
Flavonoids - chemistry
Flavonoids - pharmacology
Free Radical Scavengers - chemical synthesis
Free Radical Scavengers - chemistry
Free Radical Scavengers - pharmacology
Gynecology. Andrology. Obstetrics
Humans
interphase
Male
Male genital diseases
Medical sciences
MHY336
Molsidomine - analogs & derivatives
Molsidomine - pharmacology
Nephrology. Urinary tract diseases
oxidative stress
Oxidative Stress - drug effects
p53
Pharmacology. Drug treatments
Prostate cancer
prostatic neoplasms
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
reactive oxygen species
Reactive Oxygen Species - metabolism
Topoisomerase II inhibitor
Topoisomerase II Inhibitors - chemical synthesis
Topoisomerase II Inhibitors - chemistry
Topoisomerase II Inhibitors - pharmacology
Tumor Suppressor Protein p53 - metabolism
Tumors
Tumors of the urinary system
Up-Regulation - drug effects
Urinary tract. Prostate gland
Western blotting
title A novel epoxypropoxy flavonoid derivative and topoisomerase II inhibitor, MHY336, induces apoptosis in prostate cancer cells
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