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3-bromopyruvate and buthionine sulfoximine effectively kill anoikis-resistant hepatocellular carcinoma cells
Acquisition of anoikis resistance is a prerequisite for metastasis in hepatocellular carcinoma (HCC). However, little is known about how energy metabolism and antioxidant systems are altered in anoikis-resistant (AR) HCC cells. We evaluated anti-tumor effects of a combination treatment of 3-bromopyr...
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| Published in: | PloS one 2017-03, Vol.12 (3), p.e0174271-e0174271 |
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| container_end_page | e0174271 |
| container_issue | 3 |
| container_start_page | e0174271 |
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| creator | Lee, Minjong Jo, Ara Lee, Seulki Kim, Jong Bin Chang, Young Nam, Joon Yeul Cho, Hyeki Cho, Young Youn Cho, Eun Ju Lee, Jeong-Hoon Yu, Su Jong Yoon, Jung-Hwan Kim, Yoon Jun |
| description | Acquisition of anoikis resistance is a prerequisite for metastasis in hepatocellular carcinoma (HCC). However, little is known about how energy metabolism and antioxidant systems are altered in anoikis-resistant (AR) HCC cells. We evaluated anti-tumor effects of a combination treatment of 3-bromopyruvate (3-BP) and buthionine sulfoximine (BSO) in AR HCC cells.
We compared glycolysis, reactive oxygen species (ROS) production, and chemoresistance among Huh-BAT, HepG2 HCC cells, and the corresponding AR cells. Expression of hexokinase II, gamma-glutamylcysteine synthetase (rGCS), and epithelial-mesenchymal transition (EMT) markers in AR cells was assessed. Anti-tumor effects of a combination treatment of 3-BP and BSO were evaluated in AR cells and an HCC xenograft mouse model.
AR HCC cells showed significantly higher chemoresistance, glycolysis and lower ROS production than attached cells. Expression of hexokinase II, rGCS, and EMT markers was higher in AR HCC cells than attached cells. A combination treatment of 3-BP/BSO effectively suppressed proliferation of AR HCC cells through apoptosis by blocking glycolysis and enhancing ROS levels. In xenograft mouse models, tumor growth derived from AR HCC cells was significantly suppressed in the group treated with 3-BP/BSO compared to the group treated with 3-BP or sorafenib.
These results demonstrated that a combination treatment of 3-BP/BSO had a synergistic anti-tumor effect in an AR HCC model. This strategy may be an effective adjuvant therapy for patients with sorafenib-resistant HCC. |
| doi_str_mv | 10.1371/journal.pone.0174271 |
| format | article |
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We compared glycolysis, reactive oxygen species (ROS) production, and chemoresistance among Huh-BAT, HepG2 HCC cells, and the corresponding AR cells. Expression of hexokinase II, gamma-glutamylcysteine synthetase (rGCS), and epithelial-mesenchymal transition (EMT) markers in AR cells was assessed. Anti-tumor effects of a combination treatment of 3-BP and BSO were evaluated in AR cells and an HCC xenograft mouse model.
AR HCC cells showed significantly higher chemoresistance, glycolysis and lower ROS production than attached cells. Expression of hexokinase II, rGCS, and EMT markers was higher in AR HCC cells than attached cells. A combination treatment of 3-BP/BSO effectively suppressed proliferation of AR HCC cells through apoptosis by blocking glycolysis and enhancing ROS levels. In xenograft mouse models, tumor growth derived from AR HCC cells was significantly suppressed in the group treated with 3-BP/BSO compared to the group treated with 3-BP or sorafenib.
These results demonstrated that a combination treatment of 3-BP/BSO had a synergistic anti-tumor effect in an AR HCC model. This strategy may be an effective adjuvant therapy for patients with sorafenib-resistant HCC.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0174271</identifier><identifier>PMID: 28362858</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>5-Fluorouracil ; Acid production ; Activation ; Algae ; Alkylation ; Analysis ; Angiogenesis ; Animal models ; Anion channels ; Anoikis ; Anoikis - drug effects ; Anticancer properties ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Antioxidants ; Antitumor activity ; Apoptosis ; Argonaute 2 protein ; Arsenic ; Arsenic trioxide ; Autografts ; Biology and Life Sciences ; Biotechnology ; Breast ; Buthionine Sulfoximine - pharmacology ; Buthionine Sulfoximine - therapeutic use ; Cancer ; Cancer metastasis ; Carcinoma, Hepatocellular - drug therapy ; Care and treatment ; Cell death ; Chemotherapy ; Comparative analysis ; Cytotoxicity ; Drug resistance ; Epithelial-Mesenchymal Transition - drug effects ; Fungi ; Gene silencing ; Hep G2 Cells ; Hepatocellular carcinoma ; Humans ; Liver cancer ; Liver Neoplasms - drug therapy ; Lymphoma ; Medicine ; Medicine and Health Sciences ; Metabolism ; Neurodegenerative diseases ; Niacinamide - analogs & derivatives ; Niacinamide - pharmacology ; Niacinamide - therapeutic use ; Organs ; Oxidation ; Oxygen ; Pharmacology ; Phenylurea Compounds - pharmacology ; Phenylurea Compounds - therapeutic use ; Physical Sciences ; Physiological aspects ; Pyruvates - pharmacology ; Pyruvates - therapeutic use ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Reagents ; Research and Analysis Methods ; Respiration ; Senescence ; Survival ; Toxicity ; Transcription factors ; Tumors ; Xenografts</subject><ispartof>PloS one, 2017-03, Vol.12 (3), p.e0174271-e0174271</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Lee et al 2017 Lee et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-284715eb6a28104c4db5b12187b08c34cce84842ff9687157bba9b682364cd333</citedby><cites>FETCH-LOGICAL-c692t-284715eb6a28104c4db5b12187b08c34cce84842ff9687157bba9b682364cd333</cites><orcidid>0000-0001-9141-7773</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1882796762/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1882796762?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25752,27923,27924,37011,37012,44589,53790,53792,74897</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28362858$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ho, Yuan-Soon</contributor><creatorcontrib>Lee, Minjong</creatorcontrib><creatorcontrib>Jo, Ara</creatorcontrib><creatorcontrib>Lee, Seulki</creatorcontrib><creatorcontrib>Kim, Jong Bin</creatorcontrib><creatorcontrib>Chang, Young</creatorcontrib><creatorcontrib>Nam, Joon Yeul</creatorcontrib><creatorcontrib>Cho, Hyeki</creatorcontrib><creatorcontrib>Cho, Young Youn</creatorcontrib><creatorcontrib>Cho, Eun Ju</creatorcontrib><creatorcontrib>Lee, Jeong-Hoon</creatorcontrib><creatorcontrib>Yu, Su Jong</creatorcontrib><creatorcontrib>Yoon, Jung-Hwan</creatorcontrib><creatorcontrib>Kim, Yoon Jun</creatorcontrib><title>3-bromopyruvate and buthionine sulfoximine effectively kill anoikis-resistant hepatocellular carcinoma cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Acquisition of anoikis resistance is a prerequisite for metastasis in hepatocellular carcinoma (HCC). However, little is known about how energy metabolism and antioxidant systems are altered in anoikis-resistant (AR) HCC cells. We evaluated anti-tumor effects of a combination treatment of 3-bromopyruvate (3-BP) and buthionine sulfoximine (BSO) in AR HCC cells.
We compared glycolysis, reactive oxygen species (ROS) production, and chemoresistance among Huh-BAT, HepG2 HCC cells, and the corresponding AR cells. Expression of hexokinase II, gamma-glutamylcysteine synthetase (rGCS), and epithelial-mesenchymal transition (EMT) markers in AR cells was assessed. Anti-tumor effects of a combination treatment of 3-BP and BSO were evaluated in AR cells and an HCC xenograft mouse model.
AR HCC cells showed significantly higher chemoresistance, glycolysis and lower ROS production than attached cells. Expression of hexokinase II, rGCS, and EMT markers was higher in AR HCC cells than attached cells. A combination treatment of 3-BP/BSO effectively suppressed proliferation of AR HCC cells through apoptosis by blocking glycolysis and enhancing ROS levels. In xenograft mouse models, tumor growth derived from AR HCC cells was significantly suppressed in the group treated with 3-BP/BSO compared to the group treated with 3-BP or sorafenib.
These results demonstrated that a combination treatment of 3-BP/BSO had a synergistic anti-tumor effect in an AR HCC model. This strategy may be an effective adjuvant therapy for patients with sorafenib-resistant HCC.</description><subject>5-Fluorouracil</subject><subject>Acid production</subject><subject>Activation</subject><subject>Algae</subject><subject>Alkylation</subject><subject>Analysis</subject><subject>Angiogenesis</subject><subject>Animal models</subject><subject>Anion channels</subject><subject>Anoikis</subject><subject>Anoikis - drug effects</subject><subject>Anticancer properties</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Antioxidants</subject><subject>Antitumor activity</subject><subject>Apoptosis</subject><subject>Argonaute 2 protein</subject><subject>Arsenic</subject><subject>Arsenic trioxide</subject><subject>Autografts</subject><subject>Biology and Life Sciences</subject><subject>Biotechnology</subject><subject>Breast</subject><subject>Buthionine Sulfoximine - pharmacology</subject><subject>Buthionine Sulfoximine - therapeutic use</subject><subject>Cancer</subject><subject>Cancer metastasis</subject><subject>Carcinoma, Hepatocellular - drug therapy</subject><subject>Care and treatment</subject><subject>Cell death</subject><subject>Chemotherapy</subject><subject>Comparative analysis</subject><subject>Cytotoxicity</subject><subject>Drug resistance</subject><subject>Epithelial-Mesenchymal Transition - drug effects</subject><subject>Fungi</subject><subject>Gene silencing</subject><subject>Hep G2 Cells</subject><subject>Hepatocellular carcinoma</subject><subject>Humans</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - drug therapy</subject><subject>Lymphoma</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Metabolism</subject><subject>Neurodegenerative diseases</subject><subject>Niacinamide - analogs & derivatives</subject><subject>Niacinamide - pharmacology</subject><subject>Niacinamide - therapeutic use</subject><subject>Organs</subject><subject>Oxidation</subject><subject>Oxygen</subject><subject>Pharmacology</subject><subject>Phenylurea Compounds - pharmacology</subject><subject>Phenylurea Compounds - therapeutic use</subject><subject>Physical Sciences</subject><subject>Physiological aspects</subject><subject>Pyruvates - pharmacology</subject><subject>Pyruvates - therapeutic use</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Reagents</subject><subject>Research and Analysis Methods</subject><subject>Respiration</subject><subject>Senescence</subject><subject>Survival</subject><subject>Toxicity</subject><subject>Transcription factors</subject><subject>Tumors</subject><subject>Xenografts</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqNk1tr2zAUx83YWLtu32BshsHYHpzpZkl-GZSyS6BQ2O1VyLKcqJWtVJJD8-0nJ26JRx-GHiSOfud_LtLJstcQLCBm8NO1G3wv7WLjer0AkBHE4JPsFFYYFRQB_PTofJK9COEagBJzSp9nJ4hjinjJTzOLi9q7zm12ftjKqHPZN3k9xLVxvel1HgbbujvTjWfdtlpFs9V2l98YaxPrzI0JhdfBhCj7mK_1RkantLWDlT5X0ivTu07moym8zJ610gb9atrPst9fv_y6-F5cXn1bXpxfFopWKBaIEwZLXVOJOAREkaYua4ggZzXgChOlNCecoLatKE8kq2tZ1ZQjTIlqMMZn2duD7sa6IKZGBQE5R6yijKJELA9E4-S12HjTSb8TThqxNzi_EtJHo6wWLa4qQgmrNcCEaFVJikHNKt0ggrEESevzFG2oO90o3Ucv7Ux0ftObtVi5rSgxo4CPyXyYBLy7HXSIojNhbJjstRv2eWPIQcnLhL77B328uolayVSA6VuX4qpRVJwTzipGyZ5aPEKl1ejOqPSrWpPsM4ePM4fERH0XV3IIQSx__vh_9urPnH1_xK61tHEdnB1i-oNhDpIDqLwLwev2ockQiHEo7rshxqEQ01AktzfHD_TgdD8F-C8LPAh9</recordid><startdate>20170331</startdate><enddate>20170331</enddate><creator>Lee, Minjong</creator><creator>Jo, Ara</creator><creator>Lee, Seulki</creator><creator>Kim, Jong Bin</creator><creator>Chang, Young</creator><creator>Nam, Joon Yeul</creator><creator>Cho, Hyeki</creator><creator>Cho, Young Youn</creator><creator>Cho, Eun Ju</creator><creator>Lee, Jeong-Hoon</creator><creator>Yu, Su Jong</creator><creator>Yoon, Jung-Hwan</creator><creator>Kim, Yoon Jun</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-9141-7773</orcidid></search><sort><creationdate>20170331</creationdate><title>3-bromopyruvate and buthionine sulfoximine effectively kill anoikis-resistant hepatocellular carcinoma cells</title><author>Lee, Minjong ; Jo, Ara ; Lee, Seulki ; Kim, Jong Bin ; Chang, Young ; Nam, Joon Yeul ; Cho, Hyeki ; Cho, Young Youn ; Cho, Eun Ju ; Lee, Jeong-Hoon ; Yu, Su Jong ; Yoon, Jung-Hwan ; Kim, Yoon Jun</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-284715eb6a28104c4db5b12187b08c34cce84842ff9687157bba9b682364cd333</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>5-Fluorouracil</topic><topic>Acid production</topic><topic>Activation</topic><topic>Algae</topic><topic>Alkylation</topic><topic>Analysis</topic><topic>Angiogenesis</topic><topic>Animal models</topic><topic>Anion channels</topic><topic>Anoikis</topic><topic>Anoikis - drug effects</topic><topic>Anticancer properties</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Antioxidants</topic><topic>Antitumor activity</topic><topic>Apoptosis</topic><topic>Argonaute 2 protein</topic><topic>Arsenic</topic><topic>Arsenic trioxide</topic><topic>Autografts</topic><topic>Biology and Life Sciences</topic><topic>Biotechnology</topic><topic>Breast</topic><topic>Buthionine Sulfoximine - pharmacology</topic><topic>Buthionine Sulfoximine - therapeutic use</topic><topic>Cancer</topic><topic>Cancer metastasis</topic><topic>Carcinoma, Hepatocellular - drug therapy</topic><topic>Care and treatment</topic><topic>Cell death</topic><topic>Chemotherapy</topic><topic>Comparative analysis</topic><topic>Cytotoxicity</topic><topic>Drug resistance</topic><topic>Epithelial-Mesenchymal Transition - drug effects</topic><topic>Fungi</topic><topic>Gene silencing</topic><topic>Hep G2 Cells</topic><topic>Hepatocellular carcinoma</topic><topic>Humans</topic><topic>Liver cancer</topic><topic>Liver Neoplasms - drug therapy</topic><topic>Lymphoma</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Metabolism</topic><topic>Neurodegenerative diseases</topic><topic>Niacinamide - analogs & derivatives</topic><topic>Niacinamide - pharmacology</topic><topic>Niacinamide - therapeutic use</topic><topic>Organs</topic><topic>Oxidation</topic><topic>Oxygen</topic><topic>Pharmacology</topic><topic>Phenylurea Compounds - pharmacology</topic><topic>Phenylurea Compounds - therapeutic use</topic><topic>Physical Sciences</topic><topic>Physiological aspects</topic><topic>Pyruvates - pharmacology</topic><topic>Pyruvates - therapeutic use</topic><topic>Reactive oxygen species</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Reagents</topic><topic>Research and Analysis Methods</topic><topic>Respiration</topic><topic>Senescence</topic><topic>Survival</topic><topic>Toxicity</topic><topic>Transcription factors</topic><topic>Tumors</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Minjong</creatorcontrib><creatorcontrib>Jo, Ara</creatorcontrib><creatorcontrib>Lee, Seulki</creatorcontrib><creatorcontrib>Kim, Jong Bin</creatorcontrib><creatorcontrib>Chang, Young</creatorcontrib><creatorcontrib>Nam, Joon Yeul</creatorcontrib><creatorcontrib>Cho, Hyeki</creatorcontrib><creatorcontrib>Cho, Young Youn</creatorcontrib><creatorcontrib>Cho, Eun Ju</creatorcontrib><creatorcontrib>Lee, Jeong-Hoon</creatorcontrib><creatorcontrib>Yu, Su Jong</creatorcontrib><creatorcontrib>Yoon, Jung-Hwan</creatorcontrib><creatorcontrib>Kim, Yoon Jun</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Proquest Nursing & Allied Health Source</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Minjong</au><au>Jo, Ara</au><au>Lee, Seulki</au><au>Kim, Jong Bin</au><au>Chang, Young</au><au>Nam, Joon Yeul</au><au>Cho, Hyeki</au><au>Cho, Young Youn</au><au>Cho, Eun Ju</au><au>Lee, Jeong-Hoon</au><au>Yu, Su Jong</au><au>Yoon, Jung-Hwan</au><au>Kim, Yoon Jun</au><au>Ho, Yuan-Soon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>3-bromopyruvate and buthionine sulfoximine effectively kill anoikis-resistant hepatocellular carcinoma cells</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-03-31</date><risdate>2017</risdate><volume>12</volume><issue>3</issue><spage>e0174271</spage><epage>e0174271</epage><pages>e0174271-e0174271</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Acquisition of anoikis resistance is a prerequisite for metastasis in hepatocellular carcinoma (HCC). However, little is known about how energy metabolism and antioxidant systems are altered in anoikis-resistant (AR) HCC cells. We evaluated anti-tumor effects of a combination treatment of 3-bromopyruvate (3-BP) and buthionine sulfoximine (BSO) in AR HCC cells.
We compared glycolysis, reactive oxygen species (ROS) production, and chemoresistance among Huh-BAT, HepG2 HCC cells, and the corresponding AR cells. Expression of hexokinase II, gamma-glutamylcysteine synthetase (rGCS), and epithelial-mesenchymal transition (EMT) markers in AR cells was assessed. Anti-tumor effects of a combination treatment of 3-BP and BSO were evaluated in AR cells and an HCC xenograft mouse model.
AR HCC cells showed significantly higher chemoresistance, glycolysis and lower ROS production than attached cells. Expression of hexokinase II, rGCS, and EMT markers was higher in AR HCC cells than attached cells. A combination treatment of 3-BP/BSO effectively suppressed proliferation of AR HCC cells through apoptosis by blocking glycolysis and enhancing ROS levels. In xenograft mouse models, tumor growth derived from AR HCC cells was significantly suppressed in the group treated with 3-BP/BSO compared to the group treated with 3-BP or sorafenib.
These results demonstrated that a combination treatment of 3-BP/BSO had a synergistic anti-tumor effect in an AR HCC model. This strategy may be an effective adjuvant therapy for patients with sorafenib-resistant HCC.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28362858</pmid><doi>10.1371/journal.pone.0174271</doi><tpages>e0174271</tpages><orcidid>https://orcid.org/0000-0001-9141-7773</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2017-03, Vol.12 (3), p.e0174271-e0174271 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1882796762 |
| source | Publicly Available Content Database; PubMed Central |
| subjects | 5-Fluorouracil Acid production Activation Algae Alkylation Analysis Angiogenesis Animal models Anion channels Anoikis Anoikis - drug effects Anticancer properties Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Antioxidants Antitumor activity Apoptosis Argonaute 2 protein Arsenic Arsenic trioxide Autografts Biology and Life Sciences Biotechnology Breast Buthionine Sulfoximine - pharmacology Buthionine Sulfoximine - therapeutic use Cancer Cancer metastasis Carcinoma, Hepatocellular - drug therapy Care and treatment Cell death Chemotherapy Comparative analysis Cytotoxicity Drug resistance Epithelial-Mesenchymal Transition - drug effects Fungi Gene silencing Hep G2 Cells Hepatocellular carcinoma Humans Liver cancer Liver Neoplasms - drug therapy Lymphoma Medicine Medicine and Health Sciences Metabolism Neurodegenerative diseases Niacinamide - analogs & derivatives Niacinamide - pharmacology Niacinamide - therapeutic use Organs Oxidation Oxygen Pharmacology Phenylurea Compounds - pharmacology Phenylurea Compounds - therapeutic use Physical Sciences Physiological aspects Pyruvates - pharmacology Pyruvates - therapeutic use Reactive oxygen species Reactive Oxygen Species - metabolism Reagents Research and Analysis Methods Respiration Senescence Survival Toxicity Transcription factors Tumors Xenografts |
| title | 3-bromopyruvate and buthionine sulfoximine effectively kill anoikis-resistant hepatocellular carcinoma cells |
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