Hydroxyflutamide enhances cellular sensitivity to 5-fluorouracil by suppressing thymidylate synthase expression in bicalutamide-resistant human prostate cancer cells
We investigated the antitumor effects of combination therapy with anti-androgens and 5-fluorouracil (5-FU), and examined the underlying mechanism of the treatment. Initially, we established the bicalutamide-resistant subline CDX25R from the androgen receptor (AR)-positive human prostate cancer cell...
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| Veröffentlicht in: | International journal of oncology 2011-03, Vol.38 (3), p.665-676 |
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| container_title | International journal of oncology |
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| creator | KAWABATA, Rumi OIE, Shinji OKA, Toshinori TAKAHASHI, Masayuki KANAYAMA, Hiroomi ITOH, Kohji |
| description | We investigated the antitumor effects of combination therapy with anti-androgens and 5-fluorouracil (5-FU), and examined the underlying mechanism of the treatment. Initially, we established the bicalutamide-resistant subline CDX25R from the androgen receptor (AR)-positive human prostate cancer cell line LNCaP through continuous exposure to bicalutamide. CDX25R cells lost the ability to respond to androgens, but still expressed AR. They showed significant resistance to bicalutamide, but had high sensitivity to hydroxyflutamide (OH-flutamide) compared with LNCaP cells. The CDX25R subline was thus considered to be a suitable model for prostate cancer that has developed resistance to first-line hormonal therapy but shows sensitivity to an alternative approach. Combined treatment with 5-FU and OH-flutamide had a synergistic effect on CDX25R cells. OH-flutamide decreased expression of the transcription factor E2F1, and subsequently of thymidylate synthase (TS), in CDX25R cells but not in AR-negative DU145 cells. This suggested that OH-flutamide enhanced the growth-inhibitory activity of 5-FU in CDX25R cells by reducing TS expression through the AR pathway. Combined therapy with 5-FU and OH-flutamide may, therefore, be appropriate for patients with prostate cancer that has acquired resistance to initial hormone therapy including bicalutamide. |
| doi_str_mv | 10.3892/ijo.2011.909 |
| format | Article |
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Initially, we established the bicalutamide-resistant subline CDX25R from the androgen receptor (AR)-positive human prostate cancer cell line LNCaP through continuous exposure to bicalutamide. CDX25R cells lost the ability to respond to androgens, but still expressed AR. They showed significant resistance to bicalutamide, but had high sensitivity to hydroxyflutamide (OH-flutamide) compared with LNCaP cells. The CDX25R subline was thus considered to be a suitable model for prostate cancer that has developed resistance to first-line hormonal therapy but shows sensitivity to an alternative approach. Combined treatment with 5-FU and OH-flutamide had a synergistic effect on CDX25R cells. OH-flutamide decreased expression of the transcription factor E2F1, and subsequently of thymidylate synthase (TS), in CDX25R cells but not in AR-negative DU145 cells. This suggested that OH-flutamide enhanced the growth-inhibitory activity of 5-FU in CDX25R cells by reducing TS expression through the AR pathway. Combined therapy with 5-FU and OH-flutamide may, therefore, be appropriate for patients with prostate cancer that has acquired resistance to initial hormone therapy including bicalutamide.</description><identifier>ISSN: 1019-6439</identifier><identifier>EISSN: 1791-2423</identifier><identifier>DOI: 10.3892/ijo.2011.909</identifier><identifier>PMID: 21243325</identifier><language>eng</language><publisher>Athens: Editorial Academy of the International Journal of Oncology</publisher><subject>Androgen Antagonists - administration & dosage ; Androgen Antagonists - pharmacology ; Anilides - therapeutic use ; Antimetabolites, Antineoplastic - administration & dosage ; Antimetabolites, Antineoplastic - pharmacology ; Biological and medical sciences ; Carcinoma - drug therapy ; Carcinoma - genetics ; Carcinoma - pathology ; Cell Line, Tumor ; Drug Evaluation, Preclinical ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - genetics ; Drug Synergism ; Fluorouracil - administration & dosage ; Fluorouracil - pharmacology ; Flutamide - administration & dosage ; Flutamide - analogs & derivatives ; Flutamide - pharmacology ; Gene Expression Regulation, Enzymologic - drug effects ; Gene Expression Regulation, Neoplastic - drug effects ; Humans ; Male ; Medical sciences ; Models, Biological ; Neoplasms, Hormone-Dependent - drug therapy ; Neoplasms, Hormone-Dependent - genetics ; Nephrology. Urinary tract diseases ; Nitriles - therapeutic use ; Prostatic Neoplasms - drug therapy ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - pathology ; Thymidylate Synthase - genetics ; Thymidylate Synthase - metabolism ; Tosyl Compounds - therapeutic use ; Tumors ; Tumors of the urinary system ; Urinary tract. Prostate gland</subject><ispartof>International journal of oncology, 2011-03, Vol.38 (3), p.665-676</ispartof><rights>2015 INIST-CNRS</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c424t-3d40b39fc848f17884f118a4214d97d36022cc6eb3cd375e342ad5a7161bb7743</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23861687$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21243325$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>KAWABATA, Rumi</creatorcontrib><creatorcontrib>OIE, Shinji</creatorcontrib><creatorcontrib>OKA, Toshinori</creatorcontrib><creatorcontrib>TAKAHASHI, Masayuki</creatorcontrib><creatorcontrib>KANAYAMA, Hiroomi</creatorcontrib><creatorcontrib>ITOH, Kohji</creatorcontrib><title>Hydroxyflutamide enhances cellular sensitivity to 5-fluorouracil by suppressing thymidylate synthase expression in bicalutamide-resistant human prostate cancer cells</title><title>International journal of oncology</title><addtitle>Int J Oncol</addtitle><description>We investigated the antitumor effects of combination therapy with anti-androgens and 5-fluorouracil (5-FU), and examined the underlying mechanism of the treatment. Initially, we established the bicalutamide-resistant subline CDX25R from the androgen receptor (AR)-positive human prostate cancer cell line LNCaP through continuous exposure to bicalutamide. CDX25R cells lost the ability to respond to androgens, but still expressed AR. They showed significant resistance to bicalutamide, but had high sensitivity to hydroxyflutamide (OH-flutamide) compared with LNCaP cells. The CDX25R subline was thus considered to be a suitable model for prostate cancer that has developed resistance to first-line hormonal therapy but shows sensitivity to an alternative approach. Combined treatment with 5-FU and OH-flutamide had a synergistic effect on CDX25R cells. OH-flutamide decreased expression of the transcription factor E2F1, and subsequently of thymidylate synthase (TS), in CDX25R cells but not in AR-negative DU145 cells. This suggested that OH-flutamide enhanced the growth-inhibitory activity of 5-FU in CDX25R cells by reducing TS expression through the AR pathway. Combined therapy with 5-FU and OH-flutamide may, therefore, be appropriate for patients with prostate cancer that has acquired resistance to initial hormone therapy including bicalutamide.</description><subject>Androgen Antagonists - administration & dosage</subject><subject>Androgen Antagonists - pharmacology</subject><subject>Anilides - therapeutic use</subject><subject>Antimetabolites, Antineoplastic - administration & dosage</subject><subject>Antimetabolites, Antineoplastic - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Carcinoma - drug therapy</subject><subject>Carcinoma - genetics</subject><subject>Carcinoma - pathology</subject><subject>Cell Line, Tumor</subject><subject>Drug Evaluation, Preclinical</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Drug Synergism</subject><subject>Fluorouracil - administration & dosage</subject><subject>Fluorouracil - pharmacology</subject><subject>Flutamide - administration & dosage</subject><subject>Flutamide - analogs & derivatives</subject><subject>Flutamide - pharmacology</subject><subject>Gene Expression Regulation, Enzymologic - drug effects</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Models, Biological</subject><subject>Neoplasms, Hormone-Dependent - drug therapy</subject><subject>Neoplasms, Hormone-Dependent - genetics</subject><subject>Nephrology. Urinary tract diseases</subject><subject>Nitriles - therapeutic use</subject><subject>Prostatic Neoplasms - drug therapy</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Prostatic Neoplasms - pathology</subject><subject>Thymidylate Synthase - genetics</subject><subject>Thymidylate Synthase - metabolism</subject><subject>Tosyl Compounds - therapeutic use</subject><subject>Tumors</subject><subject>Tumors of the urinary system</subject><subject>Urinary tract. Prostate gland</subject><issn>1019-6439</issn><issn>1791-2423</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkL1OwzAUhS0EoqWwMSMvbKT4L7EzogooUiUWmCPHcYirxIlsBzUPxHviUgqTr-3vnnvuAeAaoyUVObk3235JEMbLHOUnYI55jhPCCD2NNcJ5kjGaz8CF91uESJoifA5mBBNGKUnn4Gs9Va7fTXU7BtmZSkNtG2mV9lDpth1b6aDX1ptgPk2YYOhhmkS4d_3opDItLCfox2Fw2ntjP2BopigztTJo6CcbGumj5u7w31toLCyNksdxSXw3PkgbYDN20sLB9fEam9Xehftx4S_BWS1br69-zwV4f3p8W62Tzevzy-phkyhGWEhoxVBJ81oJJmrMhWA1xkIyglmV84pmiBClMl1SVVGeasqIrFLJcYbLknNGF-DuoKuiC-90XQzOdNJNBUbFPu0ipl3s0y5i2hG_OeDDWHa6-oOP8Ubg9heQPu5cu7iT8f8cFRnOBKffeZ2N4w</recordid><startdate>20110301</startdate><enddate>20110301</enddate><creator>KAWABATA, Rumi</creator><creator>OIE, Shinji</creator><creator>OKA, Toshinori</creator><creator>TAKAHASHI, Masayuki</creator><creator>KANAYAMA, Hiroomi</creator><creator>ITOH, Kohji</creator><general>Editorial Academy of the International Journal of Oncology</general><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></search><sort><creationdate>20110301</creationdate><title>Hydroxyflutamide enhances cellular sensitivity to 5-fluorouracil by suppressing thymidylate synthase expression in bicalutamide-resistant human prostate cancer cells</title><author>KAWABATA, Rumi ; OIE, Shinji ; OKA, Toshinori ; TAKAHASHI, Masayuki ; KANAYAMA, Hiroomi ; ITOH, Kohji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c424t-3d40b39fc848f17884f118a4214d97d36022cc6eb3cd375e342ad5a7161bb7743</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Androgen Antagonists - administration & dosage</topic><topic>Androgen Antagonists - pharmacology</topic><topic>Anilides - therapeutic use</topic><topic>Antimetabolites, Antineoplastic - administration & dosage</topic><topic>Antimetabolites, Antineoplastic - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Carcinoma - drug therapy</topic><topic>Carcinoma - genetics</topic><topic>Carcinoma - pathology</topic><topic>Cell Line, Tumor</topic><topic>Drug Evaluation, Preclinical</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Drug Synergism</topic><topic>Fluorouracil - administration & dosage</topic><topic>Fluorouracil - pharmacology</topic><topic>Flutamide - administration & dosage</topic><topic>Flutamide - analogs & derivatives</topic><topic>Flutamide - pharmacology</topic><topic>Gene Expression Regulation, Enzymologic - drug effects</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Models, Biological</topic><topic>Neoplasms, Hormone-Dependent - drug therapy</topic><topic>Neoplasms, Hormone-Dependent - genetics</topic><topic>Nephrology. Urinary tract diseases</topic><topic>Nitriles - therapeutic use</topic><topic>Prostatic Neoplasms - drug therapy</topic><topic>Prostatic Neoplasms - genetics</topic><topic>Prostatic Neoplasms - pathology</topic><topic>Thymidylate Synthase - genetics</topic><topic>Thymidylate Synthase - metabolism</topic><topic>Tosyl Compounds - therapeutic use</topic><topic>Tumors</topic><topic>Tumors of the urinary system</topic><topic>Urinary tract. Prostate gland</topic><toplevel>online_resources</toplevel><creatorcontrib>KAWABATA, Rumi</creatorcontrib><creatorcontrib>OIE, Shinji</creatorcontrib><creatorcontrib>OKA, Toshinori</creatorcontrib><creatorcontrib>TAKAHASHI, Masayuki</creatorcontrib><creatorcontrib>KANAYAMA, Hiroomi</creatorcontrib><creatorcontrib>ITOH, Kohji</creatorcontrib><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><jtitle>International journal of oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>KAWABATA, Rumi</au><au>OIE, Shinji</au><au>OKA, Toshinori</au><au>TAKAHASHI, Masayuki</au><au>KANAYAMA, Hiroomi</au><au>ITOH, Kohji</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hydroxyflutamide enhances cellular sensitivity to 5-fluorouracil by suppressing thymidylate synthase expression in bicalutamide-resistant human prostate cancer cells</atitle><jtitle>International journal of oncology</jtitle><addtitle>Int J Oncol</addtitle><date>2011-03-01</date><risdate>2011</risdate><volume>38</volume><issue>3</issue><spage>665</spage><epage>676</epage><pages>665-676</pages><issn>1019-6439</issn><eissn>1791-2423</eissn><abstract>We investigated the antitumor effects of combination therapy with anti-androgens and 5-fluorouracil (5-FU), and examined the underlying mechanism of the treatment. Initially, we established the bicalutamide-resistant subline CDX25R from the androgen receptor (AR)-positive human prostate cancer cell line LNCaP through continuous exposure to bicalutamide. CDX25R cells lost the ability to respond to androgens, but still expressed AR. They showed significant resistance to bicalutamide, but had high sensitivity to hydroxyflutamide (OH-flutamide) compared with LNCaP cells. The CDX25R subline was thus considered to be a suitable model for prostate cancer that has developed resistance to first-line hormonal therapy but shows sensitivity to an alternative approach. Combined treatment with 5-FU and OH-flutamide had a synergistic effect on CDX25R cells. OH-flutamide decreased expression of the transcription factor E2F1, and subsequently of thymidylate synthase (TS), in CDX25R cells but not in AR-negative DU145 cells. This suggested that OH-flutamide enhanced the growth-inhibitory activity of 5-FU in CDX25R cells by reducing TS expression through the AR pathway. Combined therapy with 5-FU and OH-flutamide may, therefore, be appropriate for patients with prostate cancer that has acquired resistance to initial hormone therapy including bicalutamide.</abstract><cop>Athens</cop><pub>Editorial Academy of the International Journal of Oncology</pub><pmid>21243325</pmid><doi>10.3892/ijo.2011.909</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1019-6439 |
| ispartof | International journal of oncology, 2011-03, Vol.38 (3), p.665-676 |
| issn | 1019-6439 1791-2423 |
| language | eng |
| recordid | cdi_crossref_primary_10_3892_ijo_2011_909 |
| source | Spandidos Publications Journals; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Androgen Antagonists - administration & dosage Androgen Antagonists - pharmacology Anilides - therapeutic use Antimetabolites, Antineoplastic - administration & dosage Antimetabolites, Antineoplastic - pharmacology Biological and medical sciences Carcinoma - drug therapy Carcinoma - genetics Carcinoma - pathology Cell Line, Tumor Drug Evaluation, Preclinical Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Drug Synergism Fluorouracil - administration & dosage Fluorouracil - pharmacology Flutamide - administration & dosage Flutamide - analogs & derivatives Flutamide - pharmacology Gene Expression Regulation, Enzymologic - drug effects Gene Expression Regulation, Neoplastic - drug effects Humans Male Medical sciences Models, Biological Neoplasms, Hormone-Dependent - drug therapy Neoplasms, Hormone-Dependent - genetics Nephrology. Urinary tract diseases Nitriles - therapeutic use Prostatic Neoplasms - drug therapy Prostatic Neoplasms - genetics Prostatic Neoplasms - pathology Thymidylate Synthase - genetics Thymidylate Synthase - metabolism Tosyl Compounds - therapeutic use Tumors Tumors of the urinary system Urinary tract. Prostate gland |
| title | Hydroxyflutamide enhances cellular sensitivity to 5-fluorouracil by suppressing thymidylate synthase expression in bicalutamide-resistant human prostate cancer cells |
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